WO2017129991A2

WO2017129991A2 - Processes for preparing sterically congested dicarboxylic acid ligands and products thereof

Info

Publication number: WO2017129991A2
Application number: PCT/GB2017/050214
Authority: WO
Inventors: Abraham MENDOZA; Samuel Suárez PANTIGA
Original assignee: Stockholm University Holding Ab
Priority date: 2016-01-27
Filing date: 2017-01-27
Publication date: 2017-08-03
Also published as: WO2017129991A3; GB201601514D0

Abstract

There is provided herein a process for the preparation of a compound of formula I (I) or a salt thereof, wherein X¹ to X⁴, Y¹ to Y⁴, Z and n each have meanings provided in the description. There is also provided certain compounds of formula I.

Description

PROCESSES FOR PREPARING STERICALLY CONGESTED DICARBOXYLIC ACID LIGANDS AND PRODUCTS THEREOF

FIELD OF THE INVENTION

The present invention relates to new processes and new chemical compounds used in and obtained from those processes. In particular, it relates to processes for the synthesis of sterically congested dicarboxylic acid ligands, such as a,a,a',a'-tetramethyl-1 ,3- benzenedipropionic acid, novel dicarboxylic acid ligands obtained from these processes, novel metal carboxylate catalysts, and novel synthetic intermediates for use in their synthesis.

Background of the Invention The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or the common general knowledge.

Metal carboxylates are widely used as catalysts in transition metal catalysed organic synthesis. Of particular current interest in this field is the development of transition metal-catalysed C-H functionalisation processes. The use of sterically-congested metal carboxylate ligands has enabled access to a range of selective and efficient chemical transformations of this type. Among the most powerful ligands used for the formation of transition metal catalysts for C-H functionalisation is a,a,a',a'-tetramethyl-1 ,3-benzenedipropionic acid (referred to hereinafter as "espH ), which is used in the highly active dinuclear catalyst R i2(esp)2 (wherein "esp" represents a,a,a',a'-tetramethyl-1 ,3-benzenedipropionate). R i2esp2 finds particular utility in alkane C-H amination reactions, and, despite being first synthesised in 2004, is still regarded as the gold standard catalyst for this process.

Perhaps surprisingly given its relatively simple and symmetrical structure, the synthesis of espH2 represents a considerable challenge, largely due to the need to create the necessary two quaternary centres alpha to the carboxylic acid groups. This synthetic difficulty is reflected in the high purchase cost of espH2, which is considerably greater than might be expected when considering the complexity of the compound, and in the relatively small quantities of the ligand that are currently commercially available. These synthetic difficulties have also led to a lack of structural analogues of esphb having been reported.

The established, and to the best of our knowledge only, route reported for the synthesis esphb involves the steps of lithiation and nitrile hydrolysis, and so necessitates the use of both high and low temperatures, and the use of sensitive and pyrophoric reagents (see, for example: Espino et al., J. Am. Chem. Soc , 2004, 126, 15378-15379; Kornecki et al Chem, Comm. 2012, 48, 12097). The use of harsh reaction conditions and sensitive reagents in the currently-used process has considerable drawbacks for the development of a scalable route to espH2, not least due to the need to utilise specialized equipment to provide inert conditions, and the need to invest generally in the safety equipment and insurance required for handling large quantities of pyrophoric organometailics.

Thus, there exists a need for an alternative process for the synthesis of esphb that is more cost efficient and suitable for use on a large scale, such as may allow for an improved means for commercial synthesis of the ligand and, potentially, analogues thereof. Disclosure of the Invention

We have now surprisingly found a mild and scalable process that allows highly efficient access to esphb and other sterically congested dicarboxylic acid ligands. The skilled person will understand that all references herein to particular aspects of the invention include references to all embodiments, and combinations of one or more embodiments, that make up that aspect of the invention. Thus, all embodiments of particular aspects of the invention may be combined with one or more other embodiments of that aspect of the invention to form further embodiments without departing from the teaching of the invention.

In a first aspect of the invention, there is provided a process for the preparation of a compound of formula I

or a salt thereof, wherein:

X¹ and Y¹ each independently represent C1-12 alkyl optionally substituted with one or more F, and

X² and Y² each independently represent C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl or C1-3 alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F; or either or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, a 5- or 6-membered cycloalkyl group optionally substituted with one or more F;

X³ and X⁴ each independently represent H or C1-3 alkyl optionally substituted with one or more F;

Y³ and Y⁴ each independently represent H or C1-3 alkyl optionally substituted with one or more F; each Z independently represents halo, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the latter three groups are optionally substituted with one or more F; and n represents 0 to 4, which process comprises reacting a compound of formula II

wherein: each of X^1a and X^{1 b} represents an X¹ group as defined for compounds of formula I, each of Y^1a and Y^{1 b} represents a Y¹ group as defined for compounds of formula I, X^2a represents an X² group as defined for compounds of formula I, and

Y^2a represents a Y² group as defined for compounds of formula I; or either or both of X^1a and X^2a and Y^1a and Y^2a are joined together to form, together with the atom to which they are attached, a 6- or 7-membered cycloalkyi group optionally substituted with one or more F, and

X^{1 b} and Y^{1 b}each independently represent C1-12 alkyl optionally substituted with one or more F, wherein the rings formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I; and

X³, X⁴, Y³, Y⁴, Z and n are as defined for compounds of formula I, wherein the reaction is performed in the presence of a source of hydrogen peroxide, and optionally in the presence of a suitable solvent, which process may be hereinafter referred to as "the process of the invention".

Compounds employed in or produced by the processes described herein (i.e. those involving the process of the invention) may exhibit tautomerism. The process of the invention therefore encompasses the use or production of such compounds in any of their tautomeric forms, or in mixtures of any such forms.

Similarly, the compounds employed in or produced by the processes described herein (e.g. those involving the process of the invention) may also contain one or more asymmetric carbon atoms and may therefore exist as enantiomers or diastereoisomers, and may exhibit optical activity. The processes described herein thus encompass the use or production of such compounds in any of their optical or diastereoisomeric forms, or in mixtures of any such forms.

Unless otherwise specified, alkyl groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic (i.e. so forming a cycloalkyl group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl groups may also be part cyclic/acyclic. Particular alkyl groups that may be mentioned are acylic alkyl groups, such as linear (i.e. non-branched) alkyl groups. For the avoidance of doubt, particular cycloalkyl groups that may be mentioned include those in which each constituent carbon atom forms part of the ring. The term "alkenyl", when used herein, includes alkyl groups comprising at least one carbon-carbon double bond. Where possible (e.g. when the double bond is vicinally- disubstituted by different groups), these double bonds may exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention. Particular alkenyl groups that may be mentioned include linear alkenyl groups.

The term "alkynyl", when used herein, includes alkyl groups comprising at least one carbon-carbon triple bond. Particular alkynyl groups that may be mentioned include linear alkynyl groups.

The term "aryl", when used herein, includes Ce-io aromatic groups. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, be either wholly or partly aromatic. Particular Ce-io aryl groups that may be mentioned include phenyl, naphthyl, and the like. More particular aryl groups that may be mentioned include phenyl. When substituted, aryl groups may be substituted with, for example, from one to three (e.g. one or two, such as one) substituent(s). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system. The term "halo", when used herein, includes the halogen atoms fluorine (F), chlorine (CI), bromine (Br) and iodine (I). Particular halo groups that may be mentioned include F. The term "ring member" when used herein, may be understood to mean one of the atoms or groups positioned at the vertices of a cyclic group. Such groups (ring members) will typically be substituted or unsubstituted methylene groups. As such, the skilled person will understand that references to a cycloalkyi group that is one ring member larger than another will refer to larger rings containing one more such methylene group within the ring structure.

Suitable salts of compounds of formula I include base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Salts that may be employed include those of alkali metals, alkali earth metals and transition metals; in particular, lithium, sodium, potassium, magnesium, calcium salts. Such salts may exist, for example, as mono- or di- salts. Particular salts that may be mentioned include sodium and potassium di-salts.

The skilled person will understand that the substituents present in the compound of formula I obtained from the process of the invention will depend on the substituents present in the compound of II reacted, and so will be able to select the substituents for the compound of formula II accordingly.

For example, the skilled person will understand that, if in the compound of formula I required X¹ and X² are joined together to form, together with the atom to which they are attached, a 5-membered cycloalkyi group, the process will require reacting a compound of formula II wherein X^1a and X^2a are joined together to form, together with the atom to which they are attached, a 6-membered cycloalkyi group. Moreover, the skilled person will understand that groups such as X³, X⁴, Y³, Y⁴ and Z (including, for Z groups, the number and position thereof) in the compound of formula 11 may be selected in order to provide the same group(s) in the compound of formula I. In certain embodiments of the process of the invention:

X¹ and Y¹ each independently represent C1-7 alkyl (e.g. C1-6 alkyl) optionally substituted with one or more F, and

X² and Y² each independently represent C1-7 alkyl (e.g. C1-6 alkyl), C^ alkenyl, C^ alkynyl, aryl or Ci alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F, or either or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, a 5- or 6-membered cycloalkyl group optionally substituted with one or more F; and

X^{1 a}, X^{1 b}, Y^{1 a} and Y^{1 b} each independently represent C1-7 alkyl (e.g. C1-6 alkyl) optionally substituted with one or more F, and

X^2a and Y^2a each independently represent C1-7 alkyl (e.g. C1-6 alkyl), C2-5 alkenyl, C2-4 alkynyl, aryl or Ci alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F, or either or both of X^{1 a} and X^2a and Y^{1 a} and Y^2a are joined together to form, together with the atom to which they are attached, a 6- or 7-membered cycloalkyl group optionally substituted with one or more F, and X^{1 b} and Y^{1 b} each independently represent C1-6 alkyl optionally substituted with one or more F, wherein the rings formed by X^{1 a} and X^2a and Y^{1 a} and Y^2a in the compound of formula I I are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I.

In particular such embodiments (i.e. the embodiments described above), the X¹ , X^{1 a}, X^{1 b}, Y¹ , Y^{1 a} and Y^{1 b} groups may each independently represent C1-3 alkyl optionally substituted by one or more F, such as methyl, ethyl or iso-propyl (e.g. methyl).

In more particular such embodiments, the X² and X^2a and Y² and Y^2a groups may each independently represent C1-6 alkyl (including C3-6 cycloalkyl, such as C1-5 alkyl and C3-6 cycloalkyl), C2-5 alkenyl, C2-4 alkynyl, phenyl or -Ci alkyl-phenyl (i.e. benzyl), optionally substituted with one or more F.

In yet more particular such embodiments, the X² and X^2a and Y² and Y^2a groups may each independently represent C1-5 linear or branched (e.g. linear) alkyl, C5-6 cycloalkyl, C2-4 alkenyl or benzyl, such as linear C1-5 alkyl, cyclohexyl, -CH2-CHCH2 (i.e. allyl) or benzyl.

As described herein, X^{1 b} and Y^{1 b} in compounds of formula II may represent a group selected from X¹ and Y¹ groups, respectively, as defined for compounds of formula I.

The skilled person will understand that, in certain embodiments, the X^{1 b} and Y^{1 b} groups in compounds of formula II are not retained in the compound of formula I. Moreover, the skilled person will understand that, in particular such embodiments, X^1a and Y^1a may correspond to the X¹ and Y¹ groups, respectively, in compounds of formula I. Thus, in certain embodiments, X^{1 b} and Y^{1 b} may each independently represent C1-6 alkyl, such as C1-3 alkyl (e.g. methyl).

As described herein, either or both of X¹ and X² and Y¹ and Y² in the compound of formula I, and either or both of X^1a and X² and Y^1a and Y² in the compound of formula II, may be linked to form, together with the atom to which they are attached, a cycloalkyl group optionally substituted with one or more F, wherein the rings formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I. In such embodiments, X^{1 b} and Y^{1 b} may each independently represent C1-6 alkyl.

In more such particular embodiments, X^{1 b} and Y^{1 b} may each independently represent C1-3 alkyl, such as methyl. In yet more particular such embodiments, X¹ and X² and Y¹ and Y² in a compound of formula I may be each linked to form a 5-membered cycloalkyl group, and X^1a and X^2a and Y^1a and Y^2a in a compound of formula II may be each linked to form a 6-membered cycloalkyl group. In particular embodiments, X³, X⁴, Y³ and Y⁴ may each independently represent hydrogen, methyl, ethyl or /^'so-propyl, such as hydrogen or methyl (e.g. hydrogen). The skilled person will understand that where a particular substituent represents hydrogen (i.e. H) the relevant compound may be redrawn without that substituent showing.

In particular embodiments, each Z independently represents halo, Ci-e alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the latter three groups are optionally substituted with one or more F.

In more particular embodiments, each Z may independently represent halo or C1-3 alkyl, such as bromo, methyl, ethyl or /^'so-propyl (e.g. bromo or methyl, such as methyl).

Thus, in particular embodiments that may be mentioned:

X¹ , X^1a, X^{1 b}, Y\ Y^1a and Y^{1 b} each represent methyl; X² and X^2a and Y² and Y^2a each independently represent C1-7 alkyl (e.g. C1-6 alkyl), allyl or benzyl; and

X³, X⁴, Y³ and Y⁴ each represent H. In further embodiments that may be mentioned:

X¹ , X^1a, X^{1 b}, X², X^2a Y¹ , Y^1a, Y^{1 b}, Y² and Y^2a each represent methyl; and X³, X⁴, Y³ and Y⁴ represent H.

In yet further embodiments that may be mentioned: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 5-membered or 6-membered cycloalkyl, and in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 6-membered or 7-membered cycloalkyl, wherein the ring formed by X¹ and X² and Y¹ and Y² in the compound of formula I is one ring member larger than the ring formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II; and X¹ and Y¹ each represent methyl.

In yet further embodiments: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 5-membered cycloalkyl; in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 6-membered cycloalkyl; and

X^{1 b} and Y^{1 b} each represent methyl.

In particular embodiments that may be mentioned: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 5-membered cycloalkyl; in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 6-membered cycloalkyl;

X¹ and Y^{1 b} each represent methyl; X³, X⁴, Y³ and Y⁴ represent hydrogen; and n represents 0.

In further embodiments that may be mentioned: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 6-membered cycloalkyl; in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 7-membered cycloalkyl; X¹ and Y^{1 b} each represent methyl;

X³, X⁴, Y³ and Y⁴ represent hydrogen; and n represents 0.

In further embodiments that may be mentioned: in the compound of formula I, X¹ , X², Y¹ and Y² each represent methyl; in the compound of formula II, X^1a, X^2a, Y^1a and Y^2a methyl; X³, X⁴, Y³ and Y⁴ represent hydrogen; and n represents 0, more particularly wherein X^{1 b} and Y^{1 b} each represent methyl.

Particular compounds of formula I and II that may be mentioned include those wherein each corresponding pair of X¹ and Y¹ , X^1a and Y^1a and so on (including groups formed where two such groups are linked, such as the pairs of groups formed by X¹ and X² being linked and Y¹ and Y² being linked) are the same group.

For example, in certain embodiments that may be mentioned:

X¹ and Y¹ may represent the same group,

X^1a and Y^1a may represent the same group,

X^{1 b} and Y^{1 b} may represent the same group,

X² and Y² may represent the same group,

X^2a and Y^2a may represent the same group,

X³ and Y³ may represent the same group,

X⁴ and Y⁴ may represent the same group, and

wherein X¹ and X², Y¹ and Y², X^1a and X^2a, and Y^1a and Y^2a are joined together they may, in combination with the atom to which they are attached, represent the same group.

For example, for compounds of formula I, it may be stated that:

X¹ and Y¹ each represent the same C1-12 alkyl group optionally substituted with one or more F; X² and Y² represent the same group selected from C1-12 alkyl, C2-i2 alkenyl, C2-i2 alkynyl, aryl or C1-3 alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F; or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, the same 5- or 6-membered cycloalkyl group optionally substituted with one or more F;

X³ and X⁴ both represent the same group selected from H or C1-3 alkyl optionally substituted with one or more F; and

Y³ and Y⁴ both represent the same group selected from H or C1-3 alkyl optionally substituted with one or more F. The same applies to all embodiments of the compounds of the invention listed hereinabove and equally to compounds of formula II.

As such, the skilled person will understand that, when all of the pairs of substituents listed above represent the same substituent or group, the X¹ to X⁴ and the Y¹ to Y⁴ bearing carboxylic acid substituents on the aromatic ring in the compound of formula I and the X^1a to X⁴ and the Y^1a to Y⁴ bearing diketone substituents on the aromatic ring in the compound of formula II will be the same.

Depending on the type and position of the Z substituent(s), if any, the compounds of formula I and formula II may be symmetrical (i.e. having a plane of symmetry between the carboxylic acid substituents on the central ring in compounds of formula I and II). In order words, with reference to compounds of formulae I and II, the term "symmetrical" may be understood to mean that the portions of the molecules on either side of the vertical plane bisecting the central aromatic ring are identical.

Thus, in particular embodiments of the process of the invention, the compounds of formulae I and II are symmetrical.

The skilled person will understand that, in compounds of formula I, Z substituents may be positioned at the 2, 4, 5 and 6 positions of the benzene ring (as numbered with respect to the X¹ to X⁴ and Y¹ to Y⁴ substituted carboxylic acid groups, numbered sequentially from the Y¹ to Y⁴ substituted carboxylic acid group bearing carbon atom in the anticlockwise direction as depicted), and such groups may be referred to as Z Z², Z³ and Z⁴, respectively.

Thus, in a particular embodiment of the process of the invention, the process is a process for the preparation of a compound of formula la

or a salt thereof, wherein

X¹ , X², X³, X⁴, Y¹ , Y², Y³ and Y⁴ are as defined herein (i.e. in the first aspect of the invention, or any embodiment or combination of embodiments thereof); and

Z¹ , Z², Z³ and Z⁴ independently represent a group selected from Z, as defined herein, or H.

As described herein, compounds prepared using the process of the invention (i.e. compounds of formula I ; and the compounds of formula II reacted to prepare the same) may be symmetrical. Therefore, in particular embodiments that may be mentioned, Z² and Z⁴ are the same group.

In particular embodiments that may be mentioned:

Z¹ represents H, halo or Ci-3 alkyl; and

Z², Z³ and Z⁴ independently represent halo, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, wherein the latter three groups are optionally substituted with one or more F.

In more particular embodiments that be mentioned:

Z¹ represents H; and/or (e.g. and) Z², Z³ and Z⁴ each independently represent halo, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, wherein the latter three groups are optionally substituted with one or more F. In further embodiments:

Z¹ and Z³ independently represent halo or H; and

Z² and Z⁴ represent H.

In yet further embodiments: Z¹ and Z³ independently represent Br or H; and Z² and Z⁴ represent H.

In a particular embodiment that may be mentioned: Z¹ , Z² and Z⁴ represent H; and

Z³ represents Br.

In another embodiment that may be mentioned: Z¹ , Z² and Z⁴ each represent Me; and Z³ represents H.

In embodiments of the process of the invention, wherein the process is a process for the preparation of a compound of formula la, or salt thereof, the skilled person will understand that the process comprises reacting a compound of formula I la

wherein X^{1 a}, X^{1 b}, X^2a, X³, X⁴, Y^{1 a}, Y^{1 b}, Y^2a, Y³, Y⁴, Z¹ , Z², Z³ and Z⁴ are as defined herein.

In certain embodiments, Z¹ to Z⁴ each represent H.

Thus, in a particular embodiment, the process of the invention is a process for preparation of a compound of formula lb

or a salt thereof, wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³ and Y⁴ are as defined hereinabove.

In embodiments of the process of the invention, wherein the process is a process for the preparation of a compound of formula lb, or a salt thereof, the skilled person will understand that the process comprises reacting a compound of formula l ib

wherein X^{1 a}, X^{1 b}, X^2a, X³, X⁴, Y^{1 a}, Y^{1 b}, Y^2a, Y³ and Y⁴ are as defined herein. The process of the invention may be facilitated by the addition of a suitable base, which may have a catalytic effect. Thus, in a particular embodiment, the reaction is optionally performed in the presence of a suitable base B¹. In a more particular embodiment, the reaction is performed in the presence of a suitable base B¹.

Suitable bases that may be employed as B¹ in the process of the invention include inorganic bases (such as, metal carbonates, metal hydroxides, metal alkoxides and metal oxides). In particular embodiments, the suitable base B¹ is a metal hydroxide, a metal alkoxide or a metal oxide. In more particular embodiments, the suitable base B¹ is selected from the group consisting of LiOH, LiOMe, LiOEt, LiO'Bu NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt and KO'Bu, CaO, MgO and AI2O3 (i.e. alumina; in particular, basic alumina). In yet more particular embodiments that may be mentioned, the suitable base B¹ is NaOH (i.e. sodium hydroxide) or LiOH (i.e. lithium hydroxide). Most preferably, the suitable base B¹ is NaOH.

Alternatively, the process may be facilitated by the addition of a suitable acid, which may have a catalytic effect. Thus, in a further embodiment, the reaction may optionally be performed in the presence of a suitable acid A¹. In a more particular embodiment, the reaction is performed in the presence of a suitable acid A¹.

The suitable acid A¹ may be a mineral acid (such as, HCI, H2SO4, HNO3 or H3PO4) or, more particularly, an organic acid (such as, acetic acid, trifluoroacetic acid, camphor sulfonic acid or para-toluenesulfonic acid).

In particular embodiments, the acid A¹ is an organic acid. In more particular embodiments, the acid A¹ is a carboxylic acid or a sulfonic acid. In yet more particular embodiments, the acid A¹ is acetic acid, trifluoroacetic acid, camphor sulfonic acid or para-toluenesulfonic acid.

For the avoidance of doubt, the skilled person will understand that the inclusion of an acidic or basic additive and/or catalyst is not essential to the process of the invention, which may be promoted by reacting a compound of formula II in the presence of a suitable source of hydrogen peroxide, and optionally in the presence of a suitable solvent (particularly where such a solvent is present). In instances where the reaction is performed in media with no additional acidic or basic species included the reaction may be autocatalytic as carboxylic acids are formed as byproducts as the reaction progresses.

Suitable sources of hydrogen peroxide that may be mentioned include aqueous hydrogen peroxide, which can be obtained in a range of concentrations (for example, in concentrations ranging from 20% to 70% by weight, preferably 20% to 50% by weight). The skilled person will understand that a range of concentrations of aqueous hydrogen peroxide solution may be employed in the process of the invention and will be able to determine a suitable concentration for use as the source of hydrogen peroxide. A particular source of hydrogen peroxide that may be mentioned is 30% by weight aqueous hydrogen peroxide solution. In one embodiment of the process of the invention, the source of hydrogen peroxide is aqueous hydrogen peroxide.

The skilled person will understand that the process of the invention may be performed with a range of equivalents of hydrogen peroxide with respect to (i.e. relative to) the compound of formula II. In this regard, particular numbers of equivalents that may be envisaged include from about 1 to about 10 equivalents of hydrogen peroxide with respect to the compound of formula II, such as from about 2 to about 6 equivalents (e.g. from about 3 to about 5 equivalents; in particular, about 4 equivalents). In a particular embodiment, the process of the invention is performed in the presence of from about 3 to about 5 equivalents of hydrogen peroxide with respect to (i.e. relative to) the compound of formula II.

As used herein, the term "equivalents" may be understood to mean the molar amount of a given reagent used in a reaction process relative to the molar amount of another stated component of the reaction mixture (thus determining a stoichiometric ratio).

Wherever the word "about" is employed herein in the context of values, such as amounts (e.g. relative amounts of individual constituents in a composition or a component of a composition and absolute doses (including ratios) of active ingredients), temperatures, pressures, times, pH values and concentrations, it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1 %) from the numbers specified herein. For the avoidance of doubt, the term "about" may be omitted throughout.

As described herein, the process of the invention may be performed in the presence of a suitable solvent. In some cases, it is envisaged that the source of hydrogen peroxide, or, if liquid, the reagents themselves may act as a solvent for the reaction (e.g. where the source of hydrogen peroxide is aqueous hydrogen peroxide, the suitable solvent may be, or may include, water). In such cases, the process may also be performed in the absence of an additional suitable solvents.

The process of the invention may be performed in the presence of a range of solvents (e.g. in addition to a solvent present as part of the source of hydrogen peroxide, such as water), including protic and aprotic solvents. In a particular embodiment, the suitable solvent is a protic solvent. In a further embodiment, the suitable solvent is an aprotic solvent.

When the process of the invention is performed in the presence of a protic solvent, particular solvents that may be mentioned include water, methanol, ethanol, n-propanol, /^'- propanol, n-butanol and f-butanol, f-amyl alcohol (i.e. 2-methyl-2-butanol) and mixtures thereof. Particular solvents that may be mentioned include methanol and f-butanol.

When the process of the invention is performed in the presence of an aprotic solvent, particular solvents that may be mentioned include dichloromethane, dimethylsulfoxide, A/,A/-dimethylformamide and 1', 1 ', 1'-trifluorotoluene, and mixtures thereof. The skilled person will understand that the process of the invention may be performed at a range of suitable temperatures. In particular, suitable temperatures include those from about 0 °C to about 100 °C.

For example, particularly where X¹ and X² and Y¹ and Y² in the compound of formula I are not linked, the process of the invention may be performed at temperatures from about 0 °C to room temperature.

In particular, the skilled person will appreciate that it may be preferable to vary the temperature of the reaction vessel at different points to control the reaction rate; for example, during the addition of highly reactive chemical species. For example, in some cases the process of the invention may involve the addition of hydrogen peroxide at about 0 °C (i.e. at about 273 degrees Kelvin) followed by allowing the reaction to warm to room temperature for a period of time, before cooling to about 0 °C for the addition of a suitable base and subsequent warming again to room temperature.

As used herein the term "about 0 °C" may be understood to mean that the temperature of the reaction is controlled by means of (for example) an ice-water bath or cooling mantle. In particular, it is envisaged that the reaction may be cooled to temperatures within about 10 °C (for example 5 °C) of 0 °C.

As used herein the term "room temperature" may be understood to mean the ambient temperature of the room. As such, references to processes or reactions being performed at room temperature indicate that the reaction is being performed without any additional heating or cooling provided by any means other than by allowing the temperature of the reaction to equilibrate to the ambient temperature of the room. Room temperature may vary by several degrees depending on environmental conditions but it is typically in the range of about 18 °C to about 30 °C. The skilled person will appreciate that, in the context of chemical processes, the term room temperature is generally understood to mean about 25 °C.

For other processes, such as those wherein X¹ and X² and Y¹ and Y² in the compound of formula I are linked, the process may be performed at temperatures between about 40 °C and about 100 °C, such as from about 60 °C to about 100 °C (e.g. from about 80 °C to about 90 °C).

The skilled person will appreciate that the optimum parameters such as solvent choice and temperature for a given process will depend on a number of factors (e.g. substrate solubility, steric hindrance, and the activation energy of the reaction being performed) that may be particular to the substrate in question. The skilled person will be able to determine such parameters using routine experimentation and knowledge available to those skilled in the art.

In particular embodiments of the process of the invention, particularly those wherein X¹ and X² and Y¹ and Y² in the compound of formula I are not linked, particular reaction conditions that may be mentioned include performing the process at temperatures from about 0 °C to about 25 °C in the presence of methanol.

In further embodiments, particularly those wherein X¹ and X² and Y¹ and Y² in the compound of formula I are linked (for example to form a 5-membered cycloalkyl group), particular reaction conditions that may be mentioned include performing at least a part of the process at temperatures between 80 °C and 90 °C in f-butanol (for example, in refluxing f-butanol, e.g. between about 82 °C and about 83 °C). Such processes may be performed in the absence of an acidic or basic additive (i.e. in the absence of A¹ or B¹).

According to a further embodiment, there is provided the process of the invention, which further comprises the step of preparing the compound of formula II as defined hereinabove, which step comprises reacting a compound of formula Ilia

wherein X^1a, X^{1 b} and X^2a are as defined hereinabove; and a compound of formula 1Mb

(1Mb) wherein Y^1a, Y^{1 b} and Y^2a are as defined hereinabove; with a compound of formula IV

wherein:

X³, X⁴, Y³ and Y⁴, Z and n are as defined hereinabove (including wherein Z is represented as Z¹ to Z⁴, as described herein above); and

LG¹ and LG² each independently represent a suitable leaving group, wherein the reaction is performed in the presence of a suitable base B², and optionally in the presence of one or more suitable solvents. In embodiments where the process is a process for the preparation of a compound of formula la, the step of preparing a compound of formula lla as defined hereinabove, comprises reacting a compound of formula Ilia and a compound of formula lllb with a compound of formula IVa

wherein X³, X⁴, Y³, Y⁴, Z¹ , Z², Z³, Z⁴, LG¹ and LG² are as defined herein.

In embodiments where the process is a process for the preparation of a compound of formula lb, the step of preparing a compound of formula lib as defined hereinabove, comprises reacting a compound of formula Ilia and a compound of formula lllb with a compound of formula IVb

wherein X³, X⁴, Y³, Y⁴, LG¹ and LG² are as defined herein.

In certain embodiments, LG¹ and LG² may each independently be a suitable leaving group selected from halo (e.g. CI or Br) and S-alkyl/S-aryl sulphonates (e.g. OMs, OTs, OBr, ONs, such as OMs and OTs). In particular embodiments, LG¹ and LG² are independently selected from CI and Br.

In more particular embodiments that may be mentioned, LG¹ and LG² may be the same group. In certain embodiments, the suitable base B² may be a metal carbonate, metal hydroxide, metal alkoxide or metal oxide. In particular embodiments, B² may be selected from the group consisting of K₂C0₃, Na₂C0₃, Cs₂C0₃, K₃P0₄, NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt, KO'Bu, CaO, MgO and Al₂0₃ (in particular, basic alumina). In more particular embodiments, B² may be selected from the group consisting of K₂C0₃, Na₂C0₃, Cs₂C0₃ and KO'Bu (e.g. KO'Bu or K₂C0₃).

In particular embodiments that may be mentioned: LG¹ and LG² are each independently selected from the group consisting of CI, Br, I, OMs and OTs; and/or (e.g. and)

B² is selected from the group consisting of K₂C0₃, Na₂C0₃, Cs₂C0₃, K₃P0₄, NaOH, KOH and KO'Bu.

In more particular embodiments:

LG¹ and LG² are either both CI or both Br; and/or (e.g. and) B² is K₂C0₃ or KO'Bu.

In some embodiments, the step of the preparation of a compound of formula II may be performed in the presence of an additive, which additive may serve to promote the reaction. Particular additives that may be mentioned include Kl (i.e. potassium iodide).

The step of the preparation of a compound of formula II may be performed at a range of temperatures and in a range of solvents.

Particular temperatures that may be mentioned include those between about room temperature and about 100 °C, more particularly those between about room temperature and about 90 °C. The skilled person will appreciate that the necessary reagents may be combined at room temperature before the reaction is heated to a suitable temperature to promote the reaction, typically the reaction will be heated to between about 50 °C and about 100 °C (e.g between about 60 °C and about 90 °C) to promote the reaction.

Certain solvents that may be mentioned include alcohols (e.g. methanol, ethanol, /^'- propanol or f-butanol), ethers (e.g. methyl f-butyl ether or 1 ,2-dimethoxy ethane), chlorinated hydrocarbons (e.g. dichloromethane) and ketones (e.g. acetone). Particular solvents that may be mentioned are f-butanol and 1 ,2-dimethoxy ethane.

Particularly preferred conditions for the step of the preparation of a compound of formula II involve heating to reflux (i.e. around 85 °C) in 1 ,2-dimethoxyethane.

The skilled person will understand that the step of preparing a compound of formula II is performed with at least one equivalent of the compound of formula Ilia and at least one equivalent of the compound of formula lllb with respect to the compound of formula IV, IVa or IVb. In particular, the step may be performed with from about two to about ten equivalents (such as from about three to about seven, e.g. about five equivalents) of each such reagent.

As described herein above, particular compounds of formula I (and, therefore, particular compounds of formula II) that may be mentioned include those that are symmetrical. Thus, the skilled person will understand that in particular embodiments the compounds of formula Ilia and lllb may be the same.

In such embodiments, the skilled person will understand that the step of preparing a compound of formula II is performed with at least two equivalents of the diketone compound (i.e. the compound of formula Ilia and lllb) with respect to the compound of formula IV, IVa or IVb. In particular, the step may be performed with from about two to about ten equivalents (such as from about three to about seven, e.g. about five equivalents) of each such reagent.

In further embodiments of the process of the invention (in particular those wherein X¹ and X² and Y¹ and Y² in the compound of formula I, (including la or lb) (and thus also X^1a and X^2a and Y^1a and Y^2a in the compound of formula II (including lla or lib) are not linked), there is provided the process of the invention comprising the step of preparing a compound of formula II, which further comprises the step(s) of preparing the compound of formula Ilia and/or (e.g. and) the compound of formula 1Mb, which step(s) comprise(s) reacting a compound of formula V

wherein:

R^1a represents X^1a or Y^1a as hereinabove defined, as required; and R^{1 b} represents X^{1 b} or Y^{1 b} as hereinabove defined, as required, with a compound of formula VI

R-LG³ (VI) wherein:

R² represents X^2a or Y^2a as hereinabove defined, as required; and LG³ is a suitable leaving group, wherein the reaction is performed in the presence of a suitable base B³, and optionally in the presence a suitable solvent. In particular embodiments, LG³ represents suitable leaving group selected from the group consisting of halo (e.g. Br, CI and I) and S-alkyl/S-aryl sulphonates (e.g. OMs, OTs, OTf, OBs, ONs). In more particular embodiments, LG³ is selected from the group consisting of CI, Br, I, OMs and OTs (e.g. Br or I). In certain embodiments, the suitable base B³ may be a metal carbonate, metal hydroxide, metal alkoxide or metal oxide. In particular embodiments, B³ is selected from the group consisting of K₂C0₃, Na₂C0₃, Cs₂C0₃, K₃P0₄, NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt and KO'Bu, CaO, MgO or Al₂0₃ (in particular basic alumina). In more particular embodiments, B³ is selected from the group consisting of K2CO3, Na2CC>3, CS2CO3 K3PO4, NaOH and KOH (e.g. K2CO3).

Thus, in a particular embodiments that may be mentioned:

LG³ is selected from the group consisting of CI, Br, I, OMs, OTs; and/or (e.g. and)

B³ is selected from the group consisting of K2CO3, Na2CC>3, CS2CO3, K3PO4, NaOH and KOH.

In a more particular embodiment: LG³ is Br or I; and B³ is K₂C0₃.

The step of the preparation of a compound of formula Ilia and/or (e.g. and) 1Mb may be performed at a range of temperatures and in a range of solvents. Particular temperatures that may be mentioned include those between about room temperature and about 80 °C, more particularly those between about room temperature and about 60 °C. The skilled person will appreciate that the necessary reagents may be combined at room temperature before the reaction is heated to a suitable temperature to promote the reaction, typically the reaction will be heated to between about 50 °C and about 100 °C (e.g between about 50 °C and about 70 °C) to promote the reaction.

Certain solvents that may be mentioned include alcohols (e.g. methanol, ethanol, /^'- propanol or f-butanol), ethers (e.g. methyl f-butyl ether or 1 ,2-dimethoxy ethane), chlorinated hydrocarbons (e.g. dichloromethane), and ketones (e.g. acetone). A particular solvent that may be mentioned is acetone.

Particularly preferred conditions for the step of the preparation of a compound of formula II involve heating under reflux conditions in acetone (e.g. at around 56 °C). The skilled person will appreciate that the optimum parameters such as solvent choice and temperature for a given process will depend on a number of factors (e.g. substrate solubility, steric hindrance, and the activation energy of the reaction being performed) that may be particular to the substrate in question. The skilled person will be able to determine such parameters using routine experimentation and knowledge available to those skilled in the art. In certain embodiments of the process of the invention, particularly those in which X¹ and X² and Y¹ and Y² in the compound of formula I (including la or lb) (and thus also X^1a and X^2a and Y^1a and Y^2a in the compound of formula II (including lla or lib)) are not linked, the compound of formula Ilia and/or (e.g. and) 1Mb may be formed in situ (e.g. in relation to the subsequent formation of the compound of formula II). Thus, in a particular embodiment of the process of the invention, the steps of the preparing a compound of formula Ilia and/or (e.g. and) 1Mb and preparing a compound of formula II are performed as a one-pot process.

As used herein, the phrase "one pot process" may be understood to mean that two or more chemical transformations are carried out in a single reaction vessel without an intermediate purification step. Such a process may involve partial or complete evaporation of the initial reaction solvent but may not involve purification (for example by chromatography or distillation) of the intermediate compound prior to completion of the final (e.g. second) chemical transformation. In embodiments where the steps of preparing a compound of formula Ilia and/or (e.g. and) 1Mb and a compound of formula II (including lla and lib) in a one-pot process. A particular such process may comprise: i) heating a compound of V and a compound of formula VI in the presence of a suitable base (e.g. K2CO3) and a suitable solvent (e.g. acetone) at reflux and allowing the reaction to cool to room temperature; and

ii) introducing a further solvent (e.g. 1 , 2-dimethoxyethane) (optionally after the removal of the initial solvent) and a compound of formula IV (including IVa and IVb) to the reaction vessel (optionally at room temperature) then heating the reaction at reflux.

Particular compounds of formula I and (corresponding) compounds of formula II that may be mentioned include those of the examples as provided hereinbelow. Similarly particular (corresponding) compounds of formulas III to VI that may be mentioned include those of the examples as provided hereinbelow. For the avoidance of doubt, particular processes of the invention that may be mentioned include those of the examples as provided hereinbelow. According to a second aspect of the invention, there is provided a process for the preparation of a compound of formula II as defined hereinabove, wherein the process comprises the steps for preparing a compound of formula II as defined hereinabove. According to a third aspect of the invention, there is provided a process for the preparation of a compound of formula Ilia and/or (e.g. and) 1Mb as defined herein above, wherein the process comprises the step for preparing a compound of formula Ilia and/or (e.g. and) 1Mb as defined hereinabove. The skilled person will understand that compounds of formula I (i.e. samples of compounds of formula I) prepared using the process of the invention may comprise characteristic impurities resulting from the process used for their preparation, which will result in novel mixtures of compounds. According to a fourth aspect of the invention, there is provided a compound of formula I, (including la and/or lb) as defined hereinabove obtainable or obtained using a process as defined hereinabove.

In a particular embodiment of the fourth aspect of the invention, there is provided a compound of formula I (including all embodiments thereof, including la and/or lb) obtainable or obtained using a process as defined hereinabove, which compounds contains a characteristic impurity.

In a particular embodiment, the characteristic impurity may be:

a compound of one or more of formulas (a) to (c)

(a) (b) (C) wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³, Y⁴, Z and n are as defined hereinabove (i.e. for compounds of formula I in the first aspect of the invention, including all embodiments and combinations of embodiments thereof);

a compound of formula II, as defined hereinabove; a compound of formula Ilia or 1Mb, as defined hereinabove;

a compound of formula IV, as defined hereinabove;

a compound of formula V, as defined hereinabove; and/or (e.g. or)

a compound of formula VI, as defined hereinabove.

In a more particular embodiment of the fourth aspect of the invention, there is provided a compound of formula I (including all embodiments thereof, including compounds of formula la or lb) obtainable or obtained using a process as defined hereinabove, which compounds contains, as a characteristic impurity, a compound of one or more of formulas (a) to (c) (e.g. a compound of formula (a)) as defined hereinabove.

In a further embodiment, the characteristic impurity may be a by-product (i.e. a side product) resulting from the process for preparing the compound of formula II and/or the product of reacting a by-product resulting from the process for preparing the compound of formula II in the process for preparing a compound of formula I.

In view of the disclosures provided herein, the skilled person will be able to identify such by-products and reacted by-products using routine experimentation. For example, where the compound of formula II is a compound as obtained in Step 1 of Example 1 as provided hereinbelow, the by-product (i.e. a side product) resulting from the process for preparing the ompound below.

In such instances, the product of reacting a by-product resulting from the process for preparing the compound of formula II in the process for preparing a compound of formula I may be one or more of the compounds shown in Table 1 below.

0

Complete Deacylation

Table 1 : Characteristic impurities

In certain embodiments of the fourth aspect of the invention the characteristic impurity, or mixture of such impurities, is present in an amount of less than 5% (e.g. less than 1 %) by weight of a sample of the compound of formula I.

As described herein, the process of the invention may allow access to compounds that were not previously obtainable. Thus, certain compounds of formula I, and salts thereof, as described herein (such as certain compounds of formula I as described in the examples provided herein, and salts thereof) are novel, which compounds also form part of the present invention.

In a fifth as ect of the invention, there is provided a compound of formula I

as defined herein, or a salt thereof, wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³, Y⁴, Z and n are as defined hereinabove (i.e. in the first aspect of the invention, including all embodiments and combinations of embodiments thereof); but with the proviso that the compounds

salts thereof, are excluded. In an alternative fifth aspect of the invention, there is provided a compound of formula la

as defined herein, or salts thereof, wherein X¹ , X², X³, X⁴, Y\ Y², Y³, Y⁴, Z\ Z², Z³ and Z⁴ are as defined hereinabove (including all embodiments described for the first aspect of the invention), but with the provisos that: when X³, X⁴, Y³, Υ⁴· Z¹ , Z², Z³ and Z⁴ all represent hydrogen, then one or more of X¹ , X², Y¹ and Y² does not represent methyl; and when X¹ , X², Y¹ and Y² all represent methyl, and X³, X⁴, Y³, Y⁴, Z¹ , Z² and Z⁴ all represent hydrogen, then Z³ does not represent f-butyl.

In certain embodiments, there is provided a compound of formula lb

as defined herein, or salts thereof, wherein X¹, X², X³, X⁴, Y¹ , Y², Y³ and Y⁴ are as defined hereinabove (including all embodiments described for the first aspect of the invention), but with the proviso that: when X³, X⁴, Y³, Y⁴ all represent hydrogen, then one or more of X¹ , X², Y¹ and Y² does not represent methyl.

In particular embodiments of the fifth aspect of the invention (and, as described herein, particular embodiments of the first aspect of the invention), the compound of formula I is a compound of formula Ic

X³, X⁴, Y³, Y⁴, Z and n are as defined hereinabove (i.e. for compounds of formula I, including all embodiments thereof); and m represents 1 or 2.

In certain embodiments, in compounds of formula Ic, X³, X⁴, Y³ and Y⁴ each represent H and n represents 0.

In particular embodiments, m represents 1.

In alternative embodiments, m represents 2. In more particular embodiments of the fifth aspect of the invention (and, as described herein, particular embodiments of the first aspect of the invention), the compounds of formula I is a compound as shown in Table 2 (as numbered in relation to the examples), or a salt thereof.

Table 2: Particular compounds

In a particular embodiment of the fifth aspect of the invention, there is provided the compound

(which compound may be referred to herein as cpesphb), or a salt thereof. Compounds of formula II (including lla and/or lib) as described herein (such as compounds of formula II as described in the examples provided herein, and salts thereof) are also novel, which compounds also form part of the present invention.

Thus, according to a sixth aspect of the invention, there is provided a compound of formula II as defined hereinabove, including all embodiments as described for the first aspect of the invention (such as compounds of formula lla and/or lib).

In particular embodiments of the sixth aspect of the invention (and, as described herein, particular embodiments of the first aspect of the invention), the compound of formula II is a compound of formula lie

wherein X^{1 b} X³, X⁴, Y^{1 b}, Y³, Y⁴, Z and n are as defined hereinabove (including all embodiments described for the first aspect of the invention); and p represents 1 or 2.

In particular embodiments that may be mentioned:

X^{1 b} and Y^{1 b} each represent Me;

X³, X⁴, Y³ and Y⁴ each represent H; and/or (e.g. and) n represents 0.

In a particular embodiment, p represents 1.

In an alternative embodiment, p represents 2. Thus, in a particular embodiment that may be mentioned: X^{1 b} and Y^{1 b} each represent Me; X³, X⁴, Y³ and Y⁴ each represent H; n represents 0; and p represents 1.

As described herein, compounds of formula I, such as those obtained or obtainable by the processes described herein, may be useful in the synthesis of catalytic complexes.

Thus, according to a seventh aspect of the invention, there is provided a process for preparing a catalyst of formula VII

wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³, Y⁴, Z and n are as defined hereinabove (i.e. for compounds of formula I, including all embodiments thereof, as described for the first aspect of the invention), which process comprises the step of reacting a compound of formula I, as defined hereinabove, with a suitable source of rhodium, optionally in the presence of a suitable solvent, wherein the compound of formula I is prepared using a process as described hereinabove (i.e. a process of the invention, including all embodiments thereof).

In certain embodiments of the seventh aspect of the invention (e.g. those wherein the catalyst is prepared from a compound of formula la), the process is a process for the preparation of a catalyst of formula Vila

wherein X¹ , X², X³, X⁴, Y¹, Y², Y³, Y⁴, Z¹ , Z², Z³ and Z⁴ are as defined hereinabove.

In certain other embodiments of the seventh aspect of the invention (e.g. those wherein the catalyst is prepared from a compound of formula lb), the process is a process for the preparation of a catalyst of formula VI lb

wherein X¹ , X², X³, X⁴, Y¹, Y², Y³ and Y⁴ are as defined hereinabove.

Sources of rhodium that may be employed in the seventh aspect of the invention include rhodium (II) and rhodium (III) salts, such as rhodium acetate (Rh2(OAc)₄), rhodium trifluoroacetate (Rh2(02CCF3)₄) and rhodium chloride (RhCb) (optionally in the form of a hydrate, e.g. RhCI₃.xH₂0, such as RhCI₃.3H₂0). In particular embodiments of the seventh aspect of the invention, the source of rhodium is Rh₂(OAc)₄.

As described herein, the process of the seventh aspect of the invention may be performed in the presence of a suitable solvent. Particular solvents that may be mentioned include apolar aromatic solvents, such as chlorobenzene, fluorobenzene and toluene, and other high boiling solvents. Most particularly, the process may be performed in chlorobenzene.

The process of the seventh aspect of the invention may also be performed at a range of temperatures; in particular, elevated temperatures (e.g. temperatures from about 80 °C to about 150 °C, more particularly from about 100 °C to about 140 °C and most particularly between about 120 °C and 140 °C).

In particular embodiments of the seventh aspect of the invention, the process is performed (at least partially) in the presence of (i.e. in a solution of) refluxing chlorobenzene (i.e. at about 131 °C (the boiling point of chlorobenzene).

In particular embodiments of the seventh aspect of the invention the process is a process for the preparation of a catalyst of formula VI I c

wherein X³, X⁴, Y³, Y⁴, Z, m and n are as defined hereinabove (i.e. for compounds of formula lc, including all embodiments and combinations of embodiments thereof).

In particular embodiments:

X³, X⁴, Y³ and Y⁴ each represent H; and/or (e.g. and) n represents 0. In a more particular embodiment of the seventh aspect of the invention, the catalyst is

(which may be referred to herein as R i2(cpesp)2).

As described herein, as certain compounds of formula I may be novel, catalysts formed from such compounds of formula I are also novel, which novel catalysts also form part of the present invention.

Thus, according to an eighth aspect of the invention, there are also provided a catalyst of formula VII

as defined herein, wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³, Y⁴, Z and n are as defined hereinabove,

In a particular e diment, the compound

2™^J2 is also excluded. In an alternative eighth aspect of the invention, there is provided a catalyst of formula Vila as defined herein, but with the proviso that when X³, X⁴, Y³, Υ⁴· Z¹ , Z², Z³ and Z⁴ all represent hydrogen, then one or more of X¹ , X², Y¹ and Y² does not represent methyl (i.e. X¹ , X², Y¹ and Y² do not all represent methyl). In a particular embodiment of the alternative eight aspect of the invention, there is also the proviso that when X¹ , X², Y¹ and Y² all represent methyl, and X³, X⁴, Y³, Y⁴, Z\ Z² and Z⁴ all represent hydrogen, then Z³ does not represent f-butyl.

In other certain embodiments, the catalyst of formula VII is a catalyst of formula Vllb but with the proviso that when X³, X⁴, Y³ and Y⁴ all represent hydrogen, then one or more of X¹ , X², Y¹ and Y² does not represent methyl.

In particular embodiments of the eighth aspect of the invention, there is provided a catalyst of formula VI I c

wherein X³, X⁴, Y³, Y⁴, Z, m and n are as defined hereinabove, including all aspects described for the first aspect of the invention. In a certain embodiment of the eighth aspect of the invention, X³, X⁴, Y³ and Y⁴ each represent H; and/or (e.g. and) n represents 0.

In particular embodiments of the eighth aspect of the invention, the catalyst is of the formula W2Rh2, wherein W represents a compound as described in Table 2 but in dianion form.

In a more particular embodiment of the eighth aspect of the invention, the catalyst is

(which may be referred to herein as R i2(cpesp)2).

According to a ninth aspect of the invention, there is provided a process for the preparation of the novel catalysts as defined in the eight aspect of the invention, wherein the process comprises reacting a novel compound of formula I as defined in the fifth aspect of the invention with a source of rhodium, under conditions as described in the seventh aspect of the invention.

As described herein, the process of the invention may have the advantage of being more efficient and/or more suitable for use on a large scale (e.g. in a commercial production process) than processes of the prior art. In addition, the process of the invention may allow for the synthesis of new ligands and corresponding catalysts that may have the advantage of improved catalytic activity in C-H amination processes and may display improved catalytic turnover or improved performance in the preparation of challenging substrates. Figures

Figure 1 illustrates the comparative catalytic activities of R i2(cpesp)2 and R i2(esp)2 in a C-H amination process as described in Example 15 herein below.

In particular, Figure 1 shows that the use of R i2(cpesp)2 resulted in improved yields (as determined by ¹ H NMR spectroscopy using 1 ,1 ,2,2-tetrachloroethane as an internal standard) at all catalyst loadings, indicating improved catalytic turnover, which effect is particularly apparent at lower catalyst loadings. The figures illustrated by graph in Figure 1 are also listed in Table 3.

Examples The present invention will be further illustrated by reference to the following examples. General experimental procedures

All reactions were carried out under air atmosphere with non-dry solvents obtained from commercially available sources without special precautions unless otherwise stated.

Reagents and solvents methanol, ethanol, 2-butanone, 1 ,2-dimethoxyethane, diethylether, acetone, acetylacetone, potassium carbonate, potassium iodide, 2-acetycyclohexanone, α,α'-dichloro-m-xylene, α,α'-dibromo-m-xylene and hydrogen peroxide were obtained from commercially available sources and used as received.

Reactions were monitored by ¹ H-NMR analysis, or thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica plates (60F-254), using UV light as visualizing agent and a solution of KMnCU or bromocresol green and heat as developing agents. HPLC analyses were performed on the Dionex HPLC system with UV detector (UVD 170U) and mass detector (Thermo Surveyor MSQ).

Chromatographic conditions were: Waters XBridgeTM C18, 4.6 x 50 mm column, mobile phase A: 0.1 % formic acid (aq.), mobile phase B: acetonitrile, gradient: 0% to 100% B in 5 min, flow: 1 mL/min, injection volume: 3 - 20 L, detection: 220 nm. Flash silica gel chromatography was performed using E. Merck silica gel (60 A, particle size 0.043-0.063 mm). NMR spectra for the characterization of compounds were recorded at room temperature on a Bruker instrument 400 MHz (¹ H) and at 100 MHz (¹³C). Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCb (5H = 7.26 and 5c = 77.16 ppm) as internal reference, and coupling constants (ⁿJ) are given in Hz. Data are reported as follows: chemical shift, multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, hex: hexet; br: broad, m: multiplet), coupling constants (J in Hz) and integration. Carbon multiplicities were assigned by DEPT techniques. Reactions were performed in common pyrex round bottom flasks or Cronus (SMI-LabHut Ltd) 5-20 ml flat bottom vials crimped on top with 20 mm Sil/PTFE Septa. When needed, pH values were determined by using Merck MColorpHaspt pH indicator strips (pH 0-14 Universal indicator paper). Peroxide test was performed with Quantofix peroxide 1000 semi-quantitative test strips, supplied by Sigma-Aldrich, made by Macherey-Nagel.

When specified, the reaction mixture was immersed in an ultrasonic bath Badelin Sonorex Digitex. For the scaled-up alkylation reactions Buchi stirred autoclave bep 280 equipped with a 20 L steel pressure vessel type 3 was used. Example 1. Synthesis of 3,3'-(1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (espH2: Compound 2)

Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (Comp

A round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser (50 cm length) is charged at room temperature with acetylacetone (2.8 ml, 27 mmol, 2.7 equiv.), 2-butanone (13 ml) and freshly powdered anhydrous K2CO3 (3.73 g, 27 mmol, 2.7 equiv.). After 5 min under vigorous stirring (400 rpm), Mel (1.74 ml, 28 mmol, 2.8 equiv) was added to the flask at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60°C. The reaction mixture was stirred at that temperature for 6 h while progress was monitored through the analysis of aliquots by ¹ H-NMR. Then, the reaction was allowed to cool to room temperature and a solution of α,α'-dichloro-m-xylene (1.75 g, 10 mmol, 1.0 equiv.) in 1 ,2- dimethoxyethane (14 ml) was added at once, followed by a second loading of freshly powdered anhydrous K2CO3 (3.73 g, 27 mmol, 2.7 equiv.). After that the resulting suspension was warmed up to reflux in an oil bath under vigorous stirring (800 rpm). The mixture was allowed to stir for 17 h and then it was allowed to cool to room temperature and diluted with Et20 (20 ml). The suspension was filtered through a fritted plate and the solids were thoughtfully washed with acetone (2 x 20 ml) and Et20 (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was recrystallized twice from ethanol affording 3,3'-(1 ,3- phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (2.04 g, 61 %, 6.14 mmol) as a white solid. The mother liquors were concentrated and the residue recrystallized again from ethanol affording a second crop of bis-diketone 1 as a slightly yellow solid (0.421 g, 1.27 mmol, 13%).

¹H NMR (400 MHz, CDCI₃) δ = 7.13 (t, J = 7.6 Hz, 1 H), 6.92 (dd, J = 7.7, 1.8 Hz, 2H), 6.77 (t, J = 1.8 Hz, 1 H), 3.12 (s, 4H), 2.11 (s, 12H), 1.25 (s, 6H). ¹³C NMR (101 MHz, CDCI₃) δ = 207.0, 136.7, 132.0, 128.8, 128.4, 67.5, 40.2, 27.3, 18.4.

HRMS (ESI-TOF) calc'd for [C20H26O4 + Na]⁺ 331.1904; found 331.1902.

Step 2. Synthesis of 3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid) (espHz Compound 2)

A round-bottom flask was charged with 3,3'-(1 ,3-phenylenebis(methylene))bis(3- methylpentane-2,4-dione) 1 (2.00 g, 6.05 mmol, 1.0 equiv.) and dissolved in methanol 35 ml. The obtained solution was cooled to 0°C in an ice water bath. Then, hydrogen peroxide (0.686 g, 24.2 mmol, 4.0 equiv.; 30% in water) was added dropwise. The mixture was allowed to stir for 4 hours and then at room temperature a solution sodium hydroxide (30% in water) was added until pH 9-10. The reaction was allowed to stir at room temperature for 16h. The pH was checked periodically (monitored each hour until 6 h of reaction time has passed) and further additions of the based solution were needed to keep the pH value. The methanol was concentrated in rotavapor and the obtained mixture was diluted with distilled water (15 ml) and washed with diethylether (2 x 15 ml), the water phase was made acid by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (5 x 20 ml), then the organic phases were washed with HCI 1 M (2 x 20 ml), dried over Na2S0₄, filtered and concentrated in rotavapor and high-vacuum line (1 day at 40°C), affording 3,3'-(1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (esphb; 2) as white solid (1.594 g, 5.73 mmol, 95%).

¹H NMR (400 MHz, CDCI₃) δ = 7.25 - 7.17 (m, 1 H), 7.06 - 7.00 (m, 3H), 2.85 (s, 4H), 1.21 (s, 12H). ¹³C NMR (101 MHz, CDCI₃) δ = 184.3, 137.3, 131.8, 128.7, 127.6, 45.9, 43.5, 24.5. Example 2. Synthesis of 1 ,1 '-(1 ,3-phenylenebis(methylene))dicvclopentanecarboxylic acid (Compound 4)

Step 1. Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-acetylcyclohexan-1-one) (CpespHz Compound 3)

re ux

A round bottom flask equipped with a stirring bar is charged at room temperature with 2- acetylcyclohexanone (350 mg, 2.5 mmol, 2.5 equiv.) 1 ,2-dimethoxyethane (2 ml), Kl (332 mg, 2.0 mmol, 2 equiv.) α,α'-dibromo-m-xylene (263 mg, 1.0 mmol, 1.0 equiv.). After 5 min under vigorous stirring, was added to the mixture freshly powdered anhydrous K2CO3 (344 mg, 2.5 mmol, 2.5 equiv.). The suspension was allowed to stir at reflux for 17 h, after that was allowed to cool down to room temperature and diluted with diethylether (2 ml). The suspension was filtered through a fritted plate and the solids were thoughtfully washed with acetone (2 x 5 ml) and ethylacetate (2 x 5 ml). The yellow filtrate solution was concentrated in in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was recrystallized from methanol affording 2,2'-(1 ,3-phenylenebis(methylene))bis(2- acetylcyclohexan-1-one) 3 as a white solid mixture of isomers (264 mg, 69%, 0.69 mmol). ¹H NMR (400 MHz, CDCI₃) δ = 7.13 (t, J = 7.6 Hz, 1 H), 6.93 (td, J = 7.4, 1.8 Hz, 2H), 6.86 - 6.77 (m, 1 H), 3.16 - 3.02 (m, 4H), 2.58 - 2.49 (m, 2H), 2.40 - 2.20 (m, 4H), 2.14-2.07 (m, 6H), 2.04 - 1.93 (m, 2H), 1.78 - 1.54 (m, 6H), 1.40 (m, 2H). ¹³C NMR (101 MHz, CDCU) δ = 209.8, 209.8, 136.6, 136.5, 132.8, 132. , 129.2, 129.2, 128.2, 128.4, 69.1 , 42.5, 42.4, 40.2,, 34.3, 34.2, 27.4, 27.4, 27.3, 27.2, 22.6, 22.6.

HRMS (ESI-TOF) calc'd for [C24H30O4 + H]⁺ 383.2217; found 383.2215.

Step 2. 1, 1'-(1,3-phenylenebis(methylene))dicyclopentanecarboxylic acid (cpespH^ Compound 4)

A vial was charged with 2,2'-(1 ,3-phenylenebis(methylene))bis(2-acetylcyclohexan-1-one) 3 (150 mg, 0.39 mmol, 1.0 equiv.) and dissolved in warm te/f-butanol (2 ml). Hydrogen peroxide (45 μΙ, 1.56 mmol, 4.0 equiv; 30% in water) was added dropwise. The solution was allowed to stir for 16 hours at reflux. After that reaction mixture was allowed to cool down to room temperature. The solvent was concentrated in rotavapor and the obtained mixture was diluted with sodium hydroxide aqueous solution (4 ml, 10% w/w) and washed with diethylether (4 x 2 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (5 x 10 ml). Then the organic phases were dried over sodium sulfate, filtered and concentrated in vacuo (rotavapor and high vacuum). The crude was purified by flash chromatography on silica (eluent pentane / ethylacetate / formic acid 3:1 :0.1 ; Rf = 0.29) affording 1 , T-(1 ,3- phenylenebis(methylene))dicyclopentanecarboxylic acid (cpespH2, 4) as white solid (90 mg, 0.28 mmol, 71 %).

¹H NMR (400 MHz, CDCI₃) δ = 7.17 (t, J = 7.4 Hz, 1 H), 7.06 - 6.99 (m, 3H), 2.92 (s, 4H), 2.17 - 2.05 (m, 4H), 1.73 - 1.55 (m, 12H). ¹³C NMR (101 MHz, CDCI₃) δ = 182.3, 138.2, 130.7, 128.0, 127.9, 55.7, 44.3, 35.2, 24.4.

HRMS (ESI-TOF) calc'd for [C20H26O4 - H]- 329.1758; found 329.1752.

Example 3. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 6) 3,3'-(1,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione)

2C0₃, DIME reflux

A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm length) was loaded with pentane-2,4-dione (3.00 g, 30.0 mmol), acetone (30 ml), and freshly powdered potassium carbonate (4.15 g, 30.0 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then iodoethane (4.83 g, 31.0 mmol) was added at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60°C. The mixture was allowed to stir for 6 h. After that the excess of acetone was removed by distillation until ca. 5 ml were left in the flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(chloromethyl)benzene (1.751 g, 10 mmol) in 1 ,2-dimethoxyethane (4 ml) was added, and the vessel was rinsed with more 1 ,2-dimethoxyethane (2 x 10 ml) that was added into the flask. Then freshly powdered potassium carbonate (4.15 g, 30.0 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95 °C). After 17h it was allowed to cool to room temperature and diluted with diethylether:ethylacetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethylacetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane: ethylacetate 7: 1 to 3: 1) affording as a white solid 3,3'-(1 ,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione) 5 (2.54 g, 7.69 mmol, 77 % yield) (Rf = 0.33, pentane:ethylacetate 3: 1).

¹H NMR (400 MHz, CDCI₃) δ 7.12 (t, J = 7.6 Hz, 1 H), 6.87 (dd, J = 7.7, 1.8 Hz, 2H), 6.70 (d, J = 1.9 Hz, 1 H), 3.13 (s, 4H), 2.06 (s, 12H), 1.87 (q, J = 7.6 Hz, 4H), 0.83 (t, J = 7.5 Hz, 6H). ¹³C NMR (101 MHz, CDCI₃) δ 207.1 , 136.7, 131.2, 128.6, 128.3, 71.8, 36.0, 27.8, 23.3, 8.5.

HRMS (ESI-TOF) calc'd for [C22H30O4 + H]⁺ 359.2217; found 359.2223. Step 2. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 6):

5 6 A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- ethylpentane-2,4-dione) 5 (179 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath. Hydrogen peroxide (30% w in water) (227 mg, 2.000 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. Then, the mixture was cooled down to 0°C and a solution of sodium hydroxide (267 mg, 2 mmol, 4 equiv, 30% w/w in water) was added over 2 h periodically (ca. 50 mg each addition 20 min) drop by drop keeping the pH around 9-10 during the first additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 16h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed). The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethylether (2 x 10 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (4 x 20 ml), then the organic phases were washed with HCI 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high- vacuum line (1 day at 40°C). The crude was purified by flash chromatography on silica gel (pentane: ethylacetate (5% formic acid) 3: 1 ; Rf 0.27) affording 2,2'-(1 ,3- phenylenebis(methylene))bis(2-methylbutanoic acid) 6 (121 mg, 0.395 mmol, 79 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds.

¹H NMR (400 MHz, CDCI₃) δ 7.23 - 7.14 (m, 2H), 7.09 - 6.94 (m, 6H), 3.03 (d, J = 13.1 Hz, 2H), 2.93 (d, J = 13.2 Hz, 2H), 2.76 (d, J = 13.2 Hz, 2H), 2.68 (d, J = 13.7 Hz, 2H), 1.94 - 1.75 (m, 4H), 1.61 - 1.39 (m, 4H), 1.11 (s, 6H), 1.06 (s, 6H), 1.01 - 0.86 (m, 6H). ¹³C NMR (126 MHz, CDCI₃) δ 183.5, 137.3, 131.7, 128.8, 127.7, 47.9, 45.4, 31.2, 20.1 , 9.3.

HRMS (ESI-TOF) calc'd for [Ci₈H₂60₄ - H]- 305.1758; found 305.1760.

Example 4. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 8) 3,3'-(1,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione)

K₂C0_3: l, DIME reflux A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm length) was loaded with pentane-2,4-dione (1.502 g, 15.00 mmol), acetone (15.00 ml) and freshly powdered potassium carbonate (2.073 g, 15.00 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then allyl bromide (1.875 g, 15.50 mmol) was added at once and the external joint between the the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After that the excess of acetone was distilled untill ca. 3 ml were left in flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(bromomethyl)benzene (1.320 g, 5 mmol) in 1 ,2-dimethoxyethane (5 ml) was added, the vessel was rinsed with more 1 ,2-dimethoxythane (2 x 5 ml) that was added into the flask. Then freshly powdered potassium carbonate (2.073 g, 15.00 mmol) was added followed by potassium iodide (0.415 g, 2.500 mmol) and the mixture was heated to reflux in an oil bath (external temp 95°C). After 19h it was allowed to cool to room temperature and diluted with diether:ethylacetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethylacetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a crude that was purified by flash chromatography on silica (eluent pentane:ethylacetate 7: 1 to 3: 1) affording 3,3'-(1 ,3- phenylenebis(methylene))bis(3-allylpentane-2,4-dione) 7 (1.29 g, 3.37 mmol, 67.5 % yield) (Rf = 0.30, pentane:ethylacetate 3: 1) as a white solid.

¹H NMR (400 MHz, CDCI₃) δ 7.16 (t, J = 7.6 Hz, 1 H), 6.93 (dd, J = 7.7, 1.8 Hz, 2H), 6.76 (t, J = 1.8 Hz, 1 H), 5.88 - 5.43 (m, 2H), 5.30 - 5.07 (m, 4H), 3.19 (s, 4H), 2.61 (dt, J = 7.2, 1.4 Hz, 4H), 2.11 (s, 12H). ¹³C NMR (101 MHz, CDCI₃) δ 206.1 , 136.4, 132.0, 131.3, 128.5, 128.5, 1 19.5, 71.1 , 36.7, 34.9, 27.8.

HRMS (ESI-TOF) calc'd for [C24H30O4 + Na]⁺ 405.2042; found 405.2046.

Step 2. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 8)

A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- allylpentane-2,4-dione) 7 (191 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (227 mg, 2.000 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. Then, the mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (267 mg, 2.000 mmol) was added over 2h periodically (ca 55 mg each 30 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethylether (2x 10 ml). The water phase was made acid by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (4 x 20 ml), then the organic phases were washed with 2x20 ml HCI 1 M, dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line (1 day at 40°C). The crude was purified by flash chromatography on silica gel (pentane: ethylacetate (5% formic acid) 3: 1) affording 2,2'-(1 ,3-phenylenebis(methylene))bis(2- methylpent-4-enoic acid) 8 (77 mg, 0.233 mmol, 46.6 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds. ¹H NMR (400 MHz, CDCI₃) δ 8.34 (bs, 2H), 7.20 (t, J = 7.5 Hz, 1 H), 7.1 1 - 6.98 (m, 3H), 5.94 - 5.75 (m, 2H), 5.32 - 5.07 (m, 4H), 3.03 (d, J = 13.2 Hz, 1 H), 2.98 (d, J = 13.3 Hz, 1 H), 2.78 (d, J = 13.3 Hz, 1 H), 2.73 (d, J = 13.1 Hz, 1 H), 2.59 - 2.48 (m, 2H), 2.27 - 2.15 (m, 2H), 1.13 (s, 3H), 1.1 1 (s, 3H). ¹³C NMR (126 MHz, CDCI₃) δ = 182.1 , 181.9, 137.1 , 137.1 , 133.8, 133.7, 131.7, 131.6, 128.8, 128.3, 127.8, 127.7, 118.7, 118.7, 47.5, 47.4, 45.2, 45.2, 43.2, 42.5, 20.8, 20.5.

HRMS (ESI-TOF) calc'd for [C₂oH₂60₄ - H]- 329.1758; found 329.1755.

Example 5. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 10) Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-benzylpentane-2,4-dione) (Compound 9)

K₂C0_3i l. DIME reflux

A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm long) was loaded with pentane-2,4-dione (1.502 g, 15.00 mmol), acetone (15.00 ml) and freshly powdered potassium carbonate (2.073 g, 15.00 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then (bromomethyl)benzene (2.65 g, 15.50 mmol) was added at once and the external joint between the the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After that the excess of acetone was distilled untill ca. 3 ml were left in flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(bromomethyl)benzene (1.320 g, 5 mmol) in 1 ,2- dimethoxyethane (5 ml) was added the vessel was rinsed with more 1 ,2-dimethoxythane (2 x 5 ml) that was added into the flask. Then, freshly powdered potassium carbonate (2.073 g, 15.00 mmol) was added followed by potassium iodide (0.415 g, 2.500 mmol) and the mixture was heated to reflux in an oil bath (external temp 95°C). After 19h it was allowed to cool to room temperature and diluted with ethyl ether:ethyl acetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 7: 1 to 3: 1) affording a yellowish oil 3,3'-(1 ,3-phenylenebis(methylene))bis(3-benzylpentane-2,4- dione) 9 (1.90 g, 3.94 mmol, 79 % yield) (Rf = 0.36, pentane:ethyl acetate 4: 1).

¹H NMR (500 MHz, CDCI₃) δ 7.26 - 7.18 (m, 8H), 7.12 (t, J = 7.7 Hz, 1 H), 7.02 - 6.99 (m, 5H), 6.86 (dd, J = 7.7, 1.9 Hz, 2H), 6.71 (t, J = 1.9 Hz, 1 H), 3.24 (s, 4H), 3.21 (s, 4H), 2.10 (s, 12H). ¹³C NMR (126 MHz, CDCI₃) δ = 206.6, 136.4, 136.1 , 131.1 , 129.8, 129.7, 128.6, 128.5, 128.5, 126.9, 72.1 , 37.6, 37.5, 28.4.

HRMS (ESI-TOF) calc'd for [C32H34O4 + H]⁺ 483.2530; found 483.2536. Step 2. Synthesis of 3, 3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 10)

A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- ethylpentane-2,4-dione) 9 (179 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0 °C in an ice water bath and hydrogen peroxide (30% w in water) (227 mg, 2.000 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature and then at 0°C a solution of sodium hydroxide (267 mg, 2 mmol, 4 equiv, 30% w/w in water) was added over 1.5 h periodically (ca 50 mg each 20 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 16h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed). The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2 x 10 ml), the water phase was made acidic by addition of 4N HCI at 0 °C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with 2x20 ml HCI 1 M, dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line (1 day at 40°C). The crude was purified by flash chromatography on silica gel (pentane: ethyl acetate (5% formic acid) 3:1 ; Rf 0.27) affording 2,2'-(1 ,3-phenylenebis(methylene))bis(2-methylbutanoic acid) 10 (121 mg, 0.395 mmol, 79 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds. ¹H NMR (400 MHz, CDCI₃) δ 10.77 (s, 2H), 7.38 - 7.00 (m, 14H), 3.38 - 3.08 (m, 4H), 2.94 - 2.59 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H). ¹³C NMR (125 MHz, CDCI₃) δ 182.7, 181.8, 137.4, 137.2, 137.1 , 132.3, 132.0, 130.4, 130.4, 128.9, 128.9, 128.3, 128.2, 128.0, 127.9, 126.8, 49.2, 49.0, 46.3, 46.2, 46.0, 45.3, 19.9, 19.6.

HRMS (ESI-TOF) calc'd for [CasHbsCU - H]- 429.2071 ; found 429.2075.

Example 6. Synthesis of 3,3'-(1 ,3-phenylene)bis(2-cvclohexyl-2-methylpropanoic acid) (Compound 12) Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-(cyclohexylmethyl)pentane- 2,4-dione) (Compound 11)

A round bottom flask equipped with a magnetic stirrer and a reflux condenser on top was loaded with dry potassium te/f-butoxide (1.151 g, 10.26 mmol, 5.0 equiv.), tBuOH (20 ml). The mixture was allowed to stir 5 min and 3-cyclohexylpentane-2,4-dione (1.87g, 10.26 mmol, 5.0 equiv.) was added dropwise. The yellow mixture was allowed to stir at reflux for 14h. then was allowed to cool down to room temperature diluted with ethyl acetate (20 ml and filtered through a plug of Celite. The cake was washed thoroughly ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 10: 1 to 3: 1) affording as a yellowish oil 3,3'-(1 ,3- phenylenebis(methylene))bis(3-cyclohexylpentane-2,4-dione) 11 (0.60 g, 1.286 mmol, 62.7 % yield) (Rf = 0.4, pentane:ethyl acetate 6: 1).

¹H NMR (400 MHz, CDCI₃) δ 7.14 (t, J = 7.6 Hz, 1 H), 6.89 (dd, J = 7.6, 1.8 Hz, 2H), 6.76 (t, J = 1.8 Hz, 1 H), 2.77 (s, 4H), 2.07 - 1.52 (m, 20H), 1.36 - 1.20 (m, 14H).

HRMS (ESI-TOF) calc'd for [C30H42O4 + H]⁺ 467.3156; found 467.3156.

Step 2. Synthesis of 3,3'-(1,3-phenylene)bis(2-cyclohexyl-2-methylpropanoic acid) (Compound 12)

A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- cyclohexylpentane-2,4-dione) (0.233 g, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (0.227 g, 2.000 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (0.267 g, 2.000 mmol) was added over 2h periodically (ca 55 mg each 30 min) drop by drop keeping the pH around 9-10 during the initial additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2x 10 ml), the water phase was made acid by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with HC1 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high- vacuum line. The crude was purified by flash chromatography on silica gel (pentane: ethyl acetate (5% formic acid) 3: 1) affording 3,3'-(1 ,3-phenylene)bis(2-cyclohexyl-2- methylpropanoic acid) 12 (0.066 g, 0.159 mmol, 31.8 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds.

¹H NMR (400 MHz, CDCI₃) 6 7.1 1 (t, J = 7.4 Hz, 1 H), 6.94 - 6.89 (m, 2H), 6.81 (t, J = 1.9 Hz, 1 H), 3.04 (d, J = 13.0 Hz, 2H), 2.65 (dd, J = 13.0, 4.5 Hz, 2H), 1.91 - 1.66 (m, 10H), 1.53 - 1.40 (m, 2H), 1.34 - 1.02 (m, 10H), 0.98 (s, 3H), 0.96 (s, 3H). ¹³C NMR (101 MHz, CDCIs) δ 177.0, 177.0, 137.9, 137.8, 132.3, 132.0, 128.0, 127.9, 127.6, 127.6, 51.5, 51.2, 46.2, 46.1 , 43.4, 43.4, 28.9, 27.3, 27.2, 26.9, 26.8, 26.6.

HRMS (ESI-TOF) calc'd for [CasHssCU -H]^" 413.2697; found 413.2695. Example 7. Synthesis of 2,2'-(1 ,3-phenylenebis(methylene))bis(2-methylhexanoic acid) (Compound 14)

Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-butylpentane-2,4-dione) (Compound 13)

2C0₃, DME reflux A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm long) was loaded with pentane-2,4-dione (2.403 g, 24.00 mmol), acetone (12.00 ml) and freshly powdered potassium carbonate (3.32 g, 24.00 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then 1 - bromobutane (3.40 g, 24.80 mmol) was added at once and the external joint between the the reflux condeser and the flask was wrapped with teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 12 h. After that the excess of acetone was distilled until ca. 5 ml were left in flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(bromomethyl)benzene (1.056 g, 4 mmol) in 1 ,2-dimethoxyethane (5 ml) was added this vessel was rinsed with more 1 ,2-dimethoxythane (2 x 5ml) that was added into the flask. Then freshly powdered potassium carbonate (1.658 g, 12.00 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95°C). After 19h it was allowed to cool to room temperature and diluted with ethyl ether: ethyl acetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 7:1 to 3: 1) affording 3,3'-(1 ,3-phenylenebis(methylene))bis(3-butylpentane-2,4-dione) 13 (0.93 g, 2.243 mmol, 56.1 % yield) as a yellowish oil (Rf = 0.38, pentane:ethyl acetate 4:1).

¹H NMR (400 MHz, CDCI₃) δ 7.13 (t, J = 7.6 Hz, 1 H), 6.86 (dd, J = 7.7, 1.7 Hz, 2H), 6.68 (t, J = 1.9 Hz, 1 H), 3.12 (s, 4H), 2.06 (s, 12H), 1.85 - 1.74 (m, 4H), 1.35 - 1.20 (m, 8H), 0.88 (t, J = 6.7 Hz, 6H).¹³C NMR (101 MHz, CDCI₃) δ =, 206.9, 136.6, 131.0, 128.4, 128.2, 71.2, 36.5, 32.1 , 30.5, 27.5, 23.6, 22.3, 13.9.

HRMS (ESI-TOF) calc'd for [C26H38O4+ H]⁺ 415.2843; found 415.2839.

Step 2. Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-methylhexanoic acid) (Compound 14)

A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- butylpentane-2,4-dione) (207 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (227 mg, 2.000 mmol ) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0 °C, and a solution of sodium hydroxide (30% w in water) (267 mg, 2.000 mmol) was added over 2h periodically (ca 55 mg each 30 min) drop by drop keeping the pH around 9-10 during the initial additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethylether (2x 10 ml), the water phase was made acid by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (4 x 20 ml), then the organic phases were washed with HCI 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line (1 day at 40°C). The crude was purified by flash chromatography on silica gel (pentane: ethylacetate (5% formic acid) 3: 1) affording 2,2'- (1 ,3-phenylenebis(methylene))bis(2-methylhexanoic acid) 14 (135 mg, 0.372 mmol, 74.5 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds. ¹H NMR (500 MHz, CDCI₃) δ =7.19 (t, J = 7.6 Hz, 1 H), 7.06 - 6.95 (m, 3H), 3.01 (d, J = 13.2 Hz, 1 H), 2.93 (d, J = 13.2 Hz, 1 H), 2.78 (d, J = 13.2 Hz, 1 H), 2.71 (d, J = 13.2 Hz, 1 H), 1.82 - 1.70 (m, 2H), 1.50 - 1.24 (m, 10H), 1.10 (s, 3H), 1.07 (s, 3H), 1.00 - 0.88 (m, 6H). ¹³C NMR (126 MHz, CDCI₃) δ 183.8, 183.5, 137.3, 137.1 , 131.9, 131.8, 128.7, 128.7, 127.6, 47.4, 47.4, 45.5, 45.1 , 38.7, 38.2, 27.0, 27.0, 23.2, 23.2, 20.7, 20.5, 14.0.

HRMS (ESI-TOF) calc'd for [C22H34O4 -H]^" 361.2384; found 361.2385.

Example 8. Synthesis of 2,2'-(1 ,3-phenylenebis(methylene))bis(2-methylheptanoic acid) (Compound 16) Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-benzylpentane-2,4-dione) (Compound 15)

2C0₃, DME reflux

A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm long) was loaded with pentane-2,4-dione (2.403 g, 24.00 mmol), Acetone (12.00 ml) and freshly powdered potassium carbonate (3.32 g, 24.00 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then 1 - iodopentane (4.91 g, 24.80 mmol) was added at once and the external joint between the the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After that the excess of acetone was distilled untill ca. 3 ml were left in flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(bromomethyl)benzene (1.056 g, 4 mmol) in 1 ,2-dimethoxyethane (5 ml) was added this vessel was rinsed with more 1 ,2-dimethoxythane (2 x 5ml) that was added into the flask. Then freshly powdered potassium carbonate (1.658 g, 12.00 mmol) and the mixture was heated to reflux in an oil bath (external temp 95°C). After 19h it was allowed to cool to room temperature and diluted with ethyl ether:ethyl acetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oil that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 7: 1 to 3: 1) affording 3,3'- (1 ,3-phenylenebis(methylene))bis(3-pentylpentane-2,4-dione) 15 (0.78 g, 1.762 mmol, 44.1 % yield) (Rf = 0.42, pentane:ethyl acetate 4:1) as a yellow oil.

¹H NMR (500 MHz, CDCI₃) δ 7.13 (t, J = 7.6 Hz, 1 H), 6.86 (dd, J = 7.7, 1.7 Hz, 2H), 6.68 (d, J = 1.9 Hz, 1 H), 3.12 (s, 4H), 2.06 (s, 12H), 1.87 - 1.74 (m, 4H), 1.37 - 1.20 (m, 8H), 0.88 (t, J = 6.8 Hz, 6H). ¹³C NMR (126 MHz, CDCI₃) δ =207.0, 136.7, 131.1 , 128.5, 128.3, 71.3, 36.5, 32.2, 30.5, 27.6, 23.6, 22.4, 14.0.

HRMS (ESI-TOF) calc'd for [C28H42O4 + H]⁺ 443.3156; found 443.3156.

Step 2. Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-methylheptanoic acid) (Compound 16)

A vial was charged with a stirring bar, 3,3'-(1 ,3-phenylenebis(methylene))bis(3- pentylpentane-2,4-dione) 15 (221 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (227 mg, 2.00 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (267 mg, 2.00 mmol) was added over 2h periodically (ca 55 mg each 30 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17 h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2 x 20 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with HCI 1 M (2 x20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line (1 day at 40°C). The crude was purified by flash chromatography on silica gel (pentane: ethyl acetate (5% formic acid) 3: 1) affording 2,2'-(1 ,3- phenylenebis(methylene))bis(2-methylheptanoic acid) 16 (135 mg, 0.346 mmol, 69.1 % yield) as a colorless oil. TLC plates were stained using bromophenol blue and heat, yellow spots correspond to acid compounds.

¹H NMR (400 MHz, CDCI₃) δ = 1 H NMR (400 MHz, ) δ 7.18 - 7.08 (m, 1 H), 6.96 - 6.90 (m, 2H), 6.82 (s, 1 H), 2.98 (dd, J = 13.2, 2.7 Hz, 2H), 2.64 (dd, J = 13.2, 5.7 Hz, 2H), 1.81 - 1.63 (m, 2H), 1.44 - 1.15 (m, 14H), 1.06 (s, 3H), 1.05 (s, 3H). ¹³C NMR (101 MHz, CDCI₃) δ = 177.5, 177.5, 137.6, 137.5, 132.5, 132.4, 128.3, 127.8, 51.6, 47.7, 47.6, 45.7, 45.6, 39.8, 39.7, 32.4, 29.9, 24.6, 22.7, 20.9, 20.9, 14.2.

HRMS (ESI-TOF) calc'd for [C24H38O4 - H]^" 389.2697; found 389.2699.

Example 9. Synthesis of 3,3'-(2-bromo-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 18) Step 1. Synthesis of 3,3'-((2-bromo-1,3-phenylene)bis(methylene))bis(3-methylpentane- 2,4-dione) (Compound 17)

K₂C0_3: DME reflux

A one neck round bottom flask equipped with a magnetic stirrer and a Dimroth reflux condenser on top was loaded with pentane-2,4-dione (0.398 g, 3.97 mmol), acetone (3.97 ml) and freshly powdered potassium carbonate (0.549 g, 3.97 mmol). Then iodomethane (0.583 g, 4.10 mmol) was added at once and the external joint between the the reflux condeser and the flask was wrapped with teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After that the excess of acetone was distilled untill ca. 3 ml were left in flask. The residue was allowed to cool down to room temperature and 2-bromo-1 ,3-bis(bromomethyl)benzene (0.454 g, 1.324 mmol) in 1 ,2- dimethoxyethane (4 ml) was added this vessel was rinsed with more 1 ,2-dimethoxythane (2 x 3ml) that was added into the flask. Then freshly powdered potassium carbonate (0.549 g, 3.97 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95°C). After 16h it was allowed to cool to room temperature and diluted with ethyletherethylacetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethylacetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane: ethylacetate 7: 1 to 3: 1) affording 3,3'-((2-bromo-1 ,3- phenylene)bis(methylene))bis(3-methylpentane-2,4-dione) 17 (184 mg, 0.450 mmol, 33.9 % yield) (Rf = 0.31 , pentane:ethylacetate 3: 1) as a white solid.

¹H NMR (400 MHz, CDCI₃) δ 7.07 (dd, J = 8.3, 6.9 Hz, 1 H), 6.99 - 6.94 (m, 2H), 3.52 (s, 4H), 2.15 (s, 12H), 1.28 (s, 6H). ¹³C NMR (101 MHz, CDCI₃) δ = 206.9, 137.9, 130.3, 130.1 , 127.1 , 67.6, 39.0, 27.2, 17.5.

HRMS (ESI-TOF) calc'd for [C₂oH₂5Br0₄ + H]⁺ 409.1009; found 409.1012.

Step 2. Synthesis of 3,3'-(2-bromo-1,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 18)

A vial was charged with a stirring bar, 3,3'-((2-bromo-1 ,3-phenylene)bis(methylene))bis(3- methylpentane-2,4-dione) 17 (143 mg, 0.35 mmol) and dissolved in methanol (3.5 ml)The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (136 mg, 1.400 mmol)was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (187 mg, 1.400 mmol) was added over 2h periodically (ca 40 mg each 30 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2x 10 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with 2x20 ml HCI 1 M, dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line. The crude was purified by recrystallization (water: ethanol 5: 1) affording 3,3'-(2-bromo-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) 18 (77 mg, 0.216 mmol, 61.6 % yield) as a white solid.

¹H NMR (400 MHz, acetone-d₆) δ 7.26 - 7.15 (m, 3H), 3.25 (s, 4H), 1.21 (s, 12H). ¹³C NMR (101 MHz, acetone-d₆) δ 183.0, 144.0, 135.60, 131.5, 49.8, 48.8, 29.6.

HRMS (ESI-TOF) calc'd for [Ci₆H₂i Br0₄ - H]^" 355.0550; found 355.0551.

Example 10. Synthesis of 3,3'-(5-bromo-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 20) Step 1. Synthesis of 3, 3'-((5-bromo-1,3-phenylene)bis(methylene))bis(3-methylpentane- 2,4-dione) (Compound 19)

K₂C0₃, DME reflux

A one neck round bottom flask equipped with a magnetic stirrer and a Dimroth reflux condenser on top was loaded with pentane-2,4-dione (0.169 g, 1.689 mmol), acetone (1.688 ml) and freshly powdered potassium carbonate (0.233 g, 1.689 mmol). Then iodomethane (0.248 g, 1.745 mmol) was added at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After that the excess of acetone was distilled. The residue was allowed to cool down to room temperature and 1-bromo-3,5- bis(bromomethyl)benzene (0.193 g, 0.563 mmol) in 1 ,2-dimethoxyethane (3 ml) was added this vessel was rinsed with more 1 ,2-dimethoxythane (2 x 2ml) that was added into the flask. Then freshly powdered potassium carbonate (0.233 g, 1.689 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95°C). After 17h it was allowed to cool to room temperature and diluted with ethyl ether:ethyl acetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 7: 1 to 3: 1) affording 3,3'-((5-bromo-1 ,3-phenylene)bis(methylene))bis(3-methylpentane-2,4-dione) 19 (157 mg, 0.384 mmol, 68.1 % yield) (Rf = 0.31 , pentane:ethyl acetate 3: 1).

¹H NMR (500 MHz, CDCI₃) δ 7.09 (d, J = 1.6 Hz, 2H), 6.69 (t, J = 1.5 Hz, 1 H), 3.06 (s, 4H), 2.1 1 (s, 12H), 1.24 (s, 6H).¹³C NMR (126 MHz, CDCI₃) δ 206.5, 138.7, 131.7, 130.6, 122.2, 67.3, 39.5, 27.1 , 18.2.

HRMS (ESI-TOF) calc'd for [C₂oH₂5Br0₄ + H]⁺ 409.1009; found 409.1009.

Step 2. Synthesis of 3,3'-(5-bromo-1,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 20)

19 20

A vial was charged with a stirring bar, 3,3'-((2-bromo-1 ,3-phenylene)bis(methylene))bis(3- methylpentane-2,4-dione) 19 (143 mg, 0.35 mmol) and dissolved in methanol (3.5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (136 mg, 1.400 mmol)was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (187 mg, 1.400 mmol) was added over 2h periodically (ca 40 mg each 30 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethylether (2x 10 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethylether (4 x 20 ml), then the organic phases were washed with 2x20 ml HCI 1 M, dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line. The crude was purified by recrystallization (water: ethanol 5:1) affording 3,3'-(2-bromo-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) 20 (77 mg, 0.216 mmol, 61.6 % yield) as a white solid.

¹H NMR (400 MHz, CDCI₃) δ 7.16 (d, J = 1.5 Hz, 2H), 6.98 (t, J = 1.6 Hz, 1 H), 2.78 (s, 4H), 1.19 (s, 6H). ¹³C NMR (101 MHz, CDCI3) δ = 182.7, 139.6, 131.5, 130.1 , 121.5, 45.8, 43.5, 24.7.

HRMS (ESI-TOF) calc'd for [Ci₆H₂i Br0₄ - H]^" 355.0550; found 355.0548.

Example 1 1. Synthesis of 1 , T-(1 ,3-phenylenebis(methylene))bis(cvclohexane-1- carboxylic acid) (Compound 22) Step 1. Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-acetylcycloheptan-1-one) (Compound 21)

A one neck round bottom flask equipped with a magnetic stirrer was charged with 2- acetylcycloheptan-1-one (925 mg, 6.00 mmol), freshly powdered potassium carbonate (829 mg, 6.00 mmol), 1 ,2 dimethoxyethane (8 ml) and potassium iodide (498 mg, 3.00 mmol). The mixture was allowed to stir for 5 min. After that, a reflux condenser was attached on top the flask and the mixture was heated to reflux. After 15 h the mixture was allowed to cool to room temperature and diluted with ethyl ether:ethyl acetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethyl acetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow solid that was purified by flash chromatography on silica (eluent pentane:ethyl acetate 25: 1 to 3: 1) affording 2,2'-(1 ,3-phenylenebis(methylene))bis(2-acetylcycloheptan-1-one) 21 (454 mg, 1.106 mmol, 55.3 % yield) as a white solid (Rf = 0.35, pentane:ethyl acetate 3: 1).

¹H NMR (400 MHz, CDCI₃) δ 7.07 (dd, J = 8.3, 6.9 Hz, 1 H), 6.99 - 6.94 (m, 2H), 3.52 (s, 4H), 2.15 (s, 12H), 1.28 (s, 6H).

¹³C NMR (101 MHz, CDCI₃) δ 206.9, 137.9, 130.3, 130.1 , 127.1 , 67.6, 39.0, 27.2, 17.5. HRMS (ESI-TOF) calc'd for [C26H34O4 + H]⁺ 411.2530; found 41 1.2533.

Step 2. Synthesis of 1, 1'-(1,3-phenylenebis(methylene))bis(cyclohexane-1-carboxylic acid) (Compound 22)

A vial was charged with a stirring bar, 2,2'-(1 ,3-phenylenebis(methylene))bis(2- acetylcycloheptan-1-one) 21 (205 mg, 0.5 mmol) and dissolved in methanol (5 ml). The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (227 mg, 2.000 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at 40°C. Then, the mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (267 mg, 2.000 mmol) was added over 2h periodically (ca 55 mg each 30 min) drop by drop keeping the pH around 9-10 during the initial additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at 40°C for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2x 10 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with HCI 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line. The crude was purified by recrystallization from mixture hexane: ethyl acetate (7:2) affording 1 ,1 '-(1 ,3-phenylenebis(methylene))bis(cyclohexane-1-carboxylic acid) 22 (84 mg, 0.234 mmol, 47 % yield) as a white solid. 1H NMR (400 MHz, acetone-d₆) δ 7.15 - 7.07 (m, 1 H), 7.02 - 6.95 (m, 3H), 2.79 (s, 4H), 2.04 - 1.97 (m, 4H), 1.68 -1.31 (m, 4H), 1.31 - 1.16 (m, 12H). ¹³C NMR (101 MHz, acetone-de) δ 177.5, 137.9, 133.0, 129.1 , 128.2, 48.9, 47.3, 34.7, 26.7, 24.1.

HRMS (ESI-TOF) calc'd for [C22H30O4 - H]^" 357.2071 ; found 357.2068. Example 12. Synthesis of 3,3'-(2,4,6-trimethyl-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 24)

Step 1. Synthesis of 3,3'-((2,4,6-trimethyl-1,3-phenylene)bis(methylene))bis(3- meth lpentane-2,4-dione) (Compound 23)

K₂CO_¾ DIME reflux

A one neck round bottom flask equipped with a magnetic stirrer and a Dimroth reflux condenser on top was loaded with pentane-2,4-dione (3.00 g, 30.0 mmol), acetone (30 ml) and freshly powdered potassium carbonate (4.15 g, 30 mmol). Then iodomethane (2.06 ml, 33.0 mmol) was added at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the mixture was refluxed for 6 h. After the excess acetone was distilled, the residue was allowed to cool down to room temperature and solution of 2,4-bis(bromomethyl)-1 ,3,5- trimethylbenzene (3.06 g, 10 mmol) in 1 ,2-dimethoxyethane (10.0 ml) was added this vessel was rinsed with more 1 ,2-dimethoxythane (2 x 10 ml) that was added into the flask. After 5 min, another portion of freshly finely powdered potassium carbonate (4.15 g, 30.0 mmol) was added and the mixture was heated to reflux for 17h. Then the mixture was allowed to cool to room temperature and diluted with ethyl ether:ethyl acetate (1 : 1) (20 ml). The solids were filtered. The cake was washed with acetone (2 x 25 ml) and more diethylether (2 x 25 ml). The filtrate was concentrated and the product was purified on silica gel column (6: 1 pentane ethylacetate to 3: 1 pentane:ethyl acetate) (rf at 3: 1 = 0.34) affording pure 3,3'-((2,4,6-trimethyl-1 ,3-phenylene)bis(methylene))bis(3-methylpentane- 2,4-dione) 23 (1.27 g, 3.41 mmol, 34.1 % yield) was obtained as a white solid. ¹H NMR (400 MHz, CDCI₃) δ 6.80 (s, 1 H), 3.40 (s, 4H), 2.11 (s, 12H), 2.09 (s, 6H), 1.92 (s, 3H), 1.04 (s, 6H). ¹³C NMR (101 MHz, CDCI₃) δ 207.5, 137.9, 136.5, 133.6, 131.1 , 67.1 , 31.6, 27.2, 21.7, 19.0, 17.9.

HRMS (ESI-TOF) calc'd for [C23H32O4 + H]⁺ 373.2373; found 373.2371. Step 2. Synthesis of 3,3'-(2,4,6-trimethyl-1,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 24)

A vial was charged with a stirring bar, 3,3'-((2-bromo-1 ,3-phenylene)bis(methylene))bis(3- methylpentane-2,4-dione) 23 (143 mg, 0.35 mmol) and dissolved in methanol (3.5 ml)The obtained solution was cooled to 0°C in an ice water bath and hydrogen peroxide (30% w in water) (136 mg, 1.400 mmol) was added dropwise over 30 min. The mixture was allowed to stir for 6 hours at room temperature. The mixture was cooled down to 0°C, and a solution of sodium hydroxide (30% w in water) (187 mg, 1.400 mmol) was added over 2h periodically (ca 40 mg each 30 min) drop by drop keeping the pH around 9-10 during the firsts additions. During the addition a white solid precipitate is formed. The reaction was allowed to stir at room temperature for 17h. The pH was checked periodically (monitored each hour until 3 h of reaction time has passed) to keep the pH basic. The obtained mixture was diluted with distilled water (10 ml) and the excess of methanol was concentrated in rotavapor. The basic media residue was washed with diethyl ether (2x 10 ml), the water phase was made acidic by addition of 4N HCI at 0°C until pH 1. The cloudy suspension was extracted with diethyl ether (4 x 20 ml), then the organic phases were washed with 2x20 ml HCI 1 M, dried over sodium sulfate, filtered and concentrated in rotavapor and high-vacuum line. The crude was purified by recrystallization (water: ethanol 5: 1) affording 3,3'-(2-bromo-1 ,3-phenylene)bis(2,2-dimethylpropanoic acid) (77 mg, 0.216 mmol, 61.6 % yield) as a white solid. ¹H NMR (400 MHz, acetone-d6) δ 6.88 (s, 1 H), 3.12 (s, 4H), 2.29 (s, 6H), 2.20 (s, 3H), 1.19 (s, 12H). ¹³C NMR (101 MHz, acetone-d6) δ 185.6, 137.8, 135.8, 133.3, 130.8, 43.9, 38.1 , 25.3, 21.6, 19.0.

HRMS (ESI-TOF) calc'd for [C19H26O4 - H]^" 319.1915; found 319.191 1. Example 13. Scale up of the process (> 100 g) for the synthesis of esph (Compound 2)

Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (Compound 1)

In 20-L autoclave 2-butanone (1.1 L) was charged, followed by acetylacetone (240 ml_, 2.31 mol, 2.7 equiv.) and freshly powdered anhydrous K2CO3 (320 g, 2.31 mol, 2.7 equiv.). The obtained mixture was stirred (200 rpm) at room temperature for 5 min and methyl iodide (190 ml_, 3.00 mol, 3.5 equiv.) was added. The autoclave was sealed, heated to 60°C (jacket temperature) during 18 min. The reaction mixture was stirred (200 rpm) at this temperature for 23 h. Then the content of the autoclave was cooled to 25°C and a solution of α,α'-dichloro-m-xylene (150 g, 0.86 mol, 1.0 equiv.) in 1 ,2-dimethoxyethane (1.2 L) was added, followed by freshly powdered anhydrous potassium carbonate (320 g, 2.31 mol, 2.7 equiv.). The autoclave was re-sealed, heated to 85°C (jacket temperature) and stirred (300 rpm) at this temperature for 20 h. The content of the autoclave was cooled to 25°C. Then an additional amount of freshly powdered anhydrous potassium carbonate (65 g, 0.47 mol, 0.55 equiv.) was added. The autoclave re-sealed, heated to 85°C (jacket temperature) and stirred (300 rpm) at this temperature for additional 23 h. The reaction mixture was transferred from autoclave to a 6 L round bottom flask equipped with a mechanical stirrer. Additional freshly powdered anhydrous potassium carbonate (80 g, 0.58 mol, 0.68 equiv.) was added. Reaction mixture was heated to 85°C (oil bath temperature), stirred (350 rpm) at this temperature for additional 30 h. The mixture was cooled to room temperature and diluted with methyl te/f-butyl ether(1.5 L). The obtained slurry was filtered off and the filter cake was washed at first with acetone (2 x 1.5 L) and then with methyl te/f-butyl ether (2 x 1.5 L). The precipitate formed in the filtrate was filtered off and washed with methyl te/f-butyl ether (2 x 250 ml_). The resulting filtrate was concentrated and co-evaporated with ethanol (3 x 250 ml_) . The yellow crude solid was re-crystallized from ethanol (750 ml_) by heating to reflux and cooling to 4°C. The purity (HPLC) of product after the first re-crystallization was 84 area-%. The product was recrystallized from EtOH (750 ml_) a second time. Yield: 169.22 g (60%) 3,4 of white solid (dried in vacuo at 40°C for 15 h) HPLC purity: 84 area-% (220 nm).

Step 2. Synthesis of 3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid) (espH2 Compound 2)

The suspension of 3,3'-(1 ,3-phenylenebis(methylene))bis(3-methylpentane-2,4-dione) 1 (169 g, 0.51 mol, 1.0 equiv.) in MeOH (3 L) was cooled in an ice-water bath to 0°C - 5°C (internal temperature ). Hydrogen peroxide 35% aq. sol. (180 ml_, 2.05 mol, 4.0 equiv.) was added dropwise to the suspension (in 30 minutes time) and resulting mixture was stirred at 0°C - 5°C (internal temperature) for 4 h. The mixture was slowly basified till pH 10 by adding 30 % aq. NaOH at rate to keep the internal temperature below 25°C (total volume of NaOH added - 240 ml_). After that a solution of Na₂S0₃ (255 g) in water (1 L) was added to the reaction mixture and the resulting suspension was stirred at room temperature overnight. Quantifix test for peroxides was negative. Methanol was removed from quenched reaction mixture by evaporation under reduced pressure. The obtained suspension containing product was diluted with water (300 ml_). The resulting solution was cooled to 0°C - 5°C (internal temperature) in an ice-water bath and adjusted to pH 1 by addition of 4M HCI (total 4M HCI volume added - 1 L). Obtained suspension was dissolved in EtOAc (900 ml_) and formed layers were separated. The organic phase containing the product was washed with 1 M HCI (2 x 250 mL), dried over anhydrous Na2S0₄. Solution was concentrated under reduced pressure until the volume left was approximately 300 mL (the volume includes EtOAc and the crude product, the Hex:EtOAc ratio is only approximate) . To the residue, hexane (450 mL) was added. The resulting mixture was left at 4°C. The formed precipitate was filtered off and washed with cold (4°C) hexane (200 mL) on the filter (1 st crop). The filtrate was evaporated until approximately 100 mL were left and to the residue hexane (100 mL) was added. The mixture cooled in ice-water bath for 2 h. The formed solid was filtered off and washed with cold (4°C) hexane (100 mL) on the filter (2 nd crop). Yield: 1^st crop 68.41 g (57%) of white solid (dried in vacuo at 40°C for 7 h); 2^nd crop 27.09 g (23%) of white solid (dried in vacuo at 40°C for 7 h). HPLC purity of 1^st crop is 98 area-% (220 nm); 2^nd crop 95 area-% (220 nm). Yields calculated using HPLC purity correction for the starting material.

Example 14. Synthesis of a 1 , T-(1 ,3-phenylenebis(methylene))dicvclopentanecarboxylate rhodium complex (Rh2(cpesp)2; compound 25)

25

Rh₂(cpesp)₂

67%

A Schlenck flask was equipped with an addition funnel filled with a cotton plug and potassium carbonate (0.5 g) and a reflux condeser on top of the addition funnel. Under argon atmosphere the Schlenk is charged with rhodium acetate dimer (33.4 mg, 0.076 mmol), a magnetic stirrer and chlorobenzene (25 ml). To this suspension was added a solution of 1 , 1 '-(1 ,3-phenylenebis(methylene))bis(cyclopentane-1-carboxylic acid) 4 (50 mg, 0.151 mmol) dissolved in chlorobenzene (25 ml). The mixture was heated to gently reflux and the reaction monitored by TLC until no ligand was detected. The excess solvent was removed by distillation untill dryness and the residue was directly loaded on a silica chromatographic column (pentane 10: 1 EtOAc) affording R i2(cpesp)2 25 (44 mg, 0.051 mmol, 67.4 % yield).

¹H NMR (400 MHz, CDCI₃) δ 7.08 (t, J = 7.5 Hz, 1 H), 6.97 (s, 1 H), 6.88 (dd, J = 7.5, 1.8 Hz, 2H), 2.78 (s, 4H), 1.99 - 1.79 (m, 4H), 1.55 - 1.37 (m, 8H), 1.33 - 1.22 (m, 4H), 0.97 - 0.78 (m, 2H).

HRMS (ESI-TOF) calc'd for [C₄oH480₈Rh2 + Na]⁺ 885.1357; found 885.1350.

Example 15. Comparative study of the catalytic activity of Rh2(cpesp)2 (Compound 25) vs Rhi2(esp)2 in a C-H amination (nitrenoid insertion) process

The catalytic activity of Rh2(cpesp)2, at a range of catalytic loadings, was compared against the standard commercially available R i2(esp)2 catalyst in the synthesis of cyclic sulfamate

26 via C-H amination. Yields were determined by ¹ H NMR using an internal standard. General Procedure (1.00 mol%)

Inside the glovebox, a microwave vial was loaded with the stock solution of the sulfamate (0.400 ml, 0.1 mmol) in DCM were added sequentially DCM (0.060 ml), magnesium oxide (9.27 mg, 0.230 mmol equiv), Phl(OAc)₂ (0.035 g, 0.110 mmol). The vials were crimped on top and remove from the glovebox. Finally a solution of the catalyst was added (0.200 ml, 1. 00 μηιοΙ, 1.00 mol%; 0.005 M in anhydrous DCM). The resulting mixture was allowed to stir at room temperature (12 h). The reaction was diluted with CH2CI2 (4 mL), and filtered through a pad of Celite (20 x 7 mm). The filter cake was rinsed with CH2CI2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by ¹ H-NMR (CDCI3) using 1 , 1 ,2,2-tetrachloroethane as internal standard.

General Procedure (0.50 mol%)

Inside the glovebox, a microwave vial was loaded with the stock solution of the sulfamate (0.400 ml, 0.1 mmol) in DCM were added sequentially DCM (0.060 ml), magnesium oxide (9.27 mg, 0.230 mmol equiv), Phl(OAc)₂ (0.035 g, 0.110 mmol). The vials were crimped on top and remove from the glovebox. Finally a solution of the catalyst was added (0.200 ml, 0. 50 μηιοΙ, 0.05 mol%; 0.0025 M in anhydrous DCM). The resulting mixture was allowed to stir at room temperature (12 h). The reaction was diluted with CH2CI2 (4 mL), and filtered through a pad of Celite (20 x 7 mm). The filter cake was rinsed with CH2CI2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by ¹ H-NMR (CDC ) using 1 , 1 ,2,2-tetrachloroethane as internal standard. General Procedure (0. 15 mol%)

Inside the glovebox, a microwave vial was loaded with the stock solution of the sulfamate (0.400 ml, 0.1 mmol) in DCM were added sequentially DCM (0.200 ml), magnesium oxide (9.27 mg, 0.230 mmol equiv), Phl(OAc)₂ (0.035 g, 0.110 mmol). The vials were crimped on top and remove from the glovebox. Finally a solution of the catalyst was added (0.060 ml, 0.150 μηιοΙ, 0.15 mol%; 0.0025 M in anhydrous DCM). The resulting mixture was allowed to stir at room temperature (12 h). The reaction was diluted with CH2CI2 (4 mL), and filtered through a pad of Celite (20 x 7 mm). The filter cake was rinsed with CH2CI2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by ¹ H-NMR (CDCb) using 1 , 1 ,2,2-tetrachloroethane as internal standard.

General Procedure (0.05 mol%)

Inside the glovebox, a microwave vial was loaded with the stock solution of the sulfamate (0.400 ml, 0.1 mmol) in DCM were added sequentially DCM (0.240 ml), magnesium oxide (9.27 mg, 0.230 mmol equiv), Phl(OAc)₂ (0.035 g, 0.110 mmol). The vials were crimped on top and remove from the glovebox. Finally a solution of the catalyst was added (0.020 ml, 0.050 μηιοΙ, 0.05 mol%; 0.0025 M in anhydrous DCM). The resulting mixture was allowed to stir at room temperature (12 h). The reaction was diluted with CH2CI2 (4 mL), and filtered through a pad of Celite (20 x 7 mm). The filter cake was rinsed with CH2CI2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by ¹ H-NMR (CDCb) using 1 , 1 ,2,2-tetrachloroethane as internal standard.

The use R i2(cpesp)2 resulted in improved yields at all catalyst loadings, indicating improved catalytic turnover. The effect was particularly apparent at lower catalyst loadings. A summary of the comparative catalytic activity observed is provided in Table 3 below and illustrated graphically in Figure 1.

Rh₂(esp)₂ 0.15% 18% 82%

Rh2(cpesp)2 0.15% 41 % 58%

Rh₂(esp)₂ 0.05% 5% 90%

Rh2(cpesp)2 0.05% 23% 67%

Table 3. Comparative catalytic activity of Rh2(cpesp)2 and Rh2(esp)2 in the synthesis of cyclic sulfamate 26. *% Yield and recoved starting material determined by ¹ H NMR using 1 , 1 ,2,2- tetrachloroethane as internal standard.

Claims

A process for the preparation of a compound of formula I

or a salt thereof, wherein:

X¹ and Y¹ each independently represent C1-12 alkyl optionally substituted with one or more F;

X² and Y² each independently represent C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl or C1-3 alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F; or either or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, a 5- or 6-membered cycloalkyi optionally substituted with one or more F;

Y^2a represents a Y² group as defined for compounds of formula I; or either or both of X^1a and X^2a and Y^1a and Y^2a are joined together to form, together with the atom to which they are attached, a 6- or 7-membered a cycloalkyi group optionally substituted with one or more F, and

X^{1 b} and Y^{1 b} each independently represent C1-12 alkyl optionally substituted with one or more F, wherein the rings formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I; and

X³, X⁴, Y³, Y⁴, Z and n are as defined for compounds of formula I, wherein the reaction is performed in the presence of a source of hydrogen peroxide, and optionally in the presence of a suitable solvent.

2. The process according to Claim 1 , wherein:

X¹ and Y¹ each independently represent C1-7 alkyl optionally substituted with one or more F, and X² and Y² each independently represent C1-7 alkyl, C2-5 alkenyl, C2-4 alkynyl, aryl or Ci alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F, or either or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, a 5- or 6-membered cycloalkyi group optionally substituted with one or more F; and

X^{1 a}, X^{1 b}, Y^{1 a} and Y^{1 b} each independently represent C1-7 alkyl optionally substituted with one or more F, and

X^2a and Y^2a each independently represent C1-7 alkyl, C2-5 alkenyl, C2-4 alkynyl, aryl or Ci alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F, or either or both of X^{1 a} and X^2a and Y^{1 a} and Y^2a are joined together to form, together with the atom to which they are attached, a 6- or 7-membered cycloalkyi group optionally substituted with one or more F, and

X^{1 b} and Y^{1 b} each independently represent C1-6 alkyl optionally substituted with one or more F, wherein the rings formed by X^{1 a} and X^2a and Y^{1 a} and Y^2a in the compound of formula I I are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I.

3. The process according to any one of Claim 1 or Claim 2, wherein:

X¹ and Y¹ each independently represent C1-3 alkyl optionally substituted by one or more F, and

X² and Y² independently represent C1-6 alkyl, C2-5 alkenyl, C2-4 alkynyl, phenyl or Ci alkyl- phenyl, optionally substituted with one or more F, or either or both of X¹ and X² and Y¹ and Y² are joined together to form, together with the atom to which they are attached, a 5- or 6-membered cycloalkyi group optionally substituted with one or more F; and X^1a, X^{1 b}, Y^1a and Y^{1 b} each independently represent C1-3 alkyl optionally substituted by one or more F, such as methyl, ethyl or iso-propyl, and

X^2a and Y^2a independently represent C1-6 alkyl, C^ alkenyl, C^ alkynyl, phenyl or Ci alkyl- phenyl, optionally substituted with one or more F, or either or both of X^1a and X^2a and Y^1a and Y^2a are joined together to form, together with the atom to which they are attached, a 6- or 7-membered cycloalkyl group optionally substituted with one or more F, and

X^{1 b} and Y^{1 b} each independently represent C1-6 alkyl optionally substituted with one or more F, wherein the rings formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II are one ring member larger than the rings formed by X¹ and X² and Y¹ and Y² in the compound of formula I.

4. The process according to Claim 1 , wherein: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 5-membered or 6-membered cycloalkyl; in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 6-membered or 7-membered cycloalkyl, wherein the ring formed by X¹ and X² and Y¹ and Y² in the compound of formula I is one ring member larger than the ring formed by X^1a and X^2a and Y^1a and Y^2a in the compound of formula II; and X^{1 b} and Y^{1 b} each represent methyl.

5. The process according to Claim 1 or Claim 4, wherein: in the compound of formula I, X¹ and X² and Y¹ and Y² are each joined together to form a 5-membered cycloalkyl; in the compound of formula II, X^1a and X^2a and Y^1a and Y^2a are each joined together to form a 6-membered cycloalkyl; and

Xib and Yib each represent methyl.

6. The process according to any preceding claim, wherein the compounds of formulae I and II are symmetrical.

7. The process according to any of the preceding claims, wherein X³, X⁴, Y³ and Y⁴ represent H.

8. The process according to any preceding claim, wherein the process is a process for the preparation of a compound of formula la

(la) or a salt thereof, which process comprises reacting a compound of formula lla

wherein: X¹ , X^1a, X^{1 b}, X², X^2a, X³, X⁴, Y\ Y^1a, Y^{1 b}, Y², Y^2a, Y³ and Y⁴ are as defined in any preceding claim; and Z¹ , Z², Z³ and Z⁴ independently represent Z or H, wherein Z is as defined in any preceding claim. 9. The process according to Claim 8, wherein: Z¹ represents H, halo or Ci-3 alkyl; and

10. The process according to Claim 9, wherein: Z¹ and Z³ independently represent Br or H; and

Z² and Z⁴ represent H.

1 1. The process according to Claim 9, wherein Z¹ , Z² and Z⁴ represent H; and

Z³ represents Br.

12. The process according to Claim 9, wherein:

Z¹ , Z² and Z⁴ each represent Me; and Z³ represents H. 13. The process according to any one of Claims 1 to 8, wherein the process is a process for the preparation of a compound of formula lb

or a salt thereof, which process comprises reacting a compound of formula lib,

wherein:

X¹ , X², X³, X⁴, Y¹ , Y², Y³ and Y⁴ are as defined in any preceding claim; _xia _xi b _X2a _χ3 _χ4 γΐ_{3 Y}i b γ2₃ γ3 _and γ4 _{are as de}fi_ned in any preceding claim; and Z¹ , Z², Z³ and Z⁴ independently represent Z or H, wherein Z is as defined in any preceding claim.

14. The process according to any of the preceding claims, wherein the reaction is performed in the presence of a suitable base B¹.

15. The process according to Claim 14, wherein the base B¹ is a metal hydroxide, a metal alkoxide or a metal oxide.

16. The process according to Claim 14 or Claim 15, wherein the base B¹ is selected from the group consisting of LiOH, LiOMe, LiOEt, LiO'Bu, NaOH, NaOMe, NaOEt, NaO'Bu,

KOH, KOMe, KOEt and KO'Bu, CaO, MgO and Al₂0₃.

17. The process according to any one of Claims 14 to 16, wherein the suitable base B¹ is NaOH.

18. The process according to any one of Claims 1 to 13, wherein the reaction is performed in the presence of a suitable acid A¹.

19. The process according to Claim 18, wherein the acid A¹ is an organic acid.

20. The process according to Claim 18 or Claim 19, wherein the acid A¹ is acetic acid, trifuoroacetic acid, camphor sulfonic acid or para-toluene sulfonic acid.

21. The process according to any preceding claim, wherein the source of hydrogen peroxide is aqueous hydrogen peroxide. 22. The process according to any preceding claim, wherein the reaction is performed in the presence of from about 3 to about 5 equivalents of hydrogen peroxide.

23. The process according to any one of Claims 1 to 22, wherein the suitable solvent is a protic solvent.

24. The process according Claim 23, wherein the suitable solvent is selected from the group consisting of water, methanol, ethanol, n-propanol /^'-propanol, n-butanol and t- butanol, f-amyl alcohol and mixtures thereof. 25. The process according to any one of Claims 1 to 22, wherein the suitable solvent is an aprotic solvent.

26. The process according Claim 25, wherein the suitable solvent is selected from the group consisting of dichloromethane, dimethylsulfoxide, A/,A/-dimethylformamide and 1 ',1 ', 1'-trifluorotoluene, and mixtures thereof.

27. A process according to any preceding claim, which further comprises the step of preparing the compound of formula II as defined in any preceding claim, which step comprises reacting a compound of formula Ilia

wherein X , X¹ and X^2a are as defined in any one of the preceding claims; and a compound of formula 1Mb

wherein Y^1a, Y^{1 b} and Y^2a are as defined in any one of the preceding claims; with a compound of formula IV

wherein:

X³, X⁴, Y³ and Y⁴, Z and n are as defined for compounds of formula II in any one of the preceding claims; and

LG¹ and LG² each independently represent a suitable leaving group, wherein the reaction is performed in the presence of a suitable base B², and optionally in the presence of one or more suitable solvents.

28. The process according to Claim 27, wherein the reaction is performed with at least one equivalent of the compound of formula Ilia and at least one equivalent of the compound of formula 1Mb with respect to the compound of formula IV.

29. The process according to any one of Claims 27 or 28, wherein: LG¹ and LG² are each independently selected from the group consisting of CI, Br, I, OMs and OTs; and B² is selected from the group consisting of K₂C0₃, Na₂C0₃, Cs₂C0₃, K₃P0₄, NaOH, KO'Bu.

30. The process according to any one of Claims 27 to 29, wherein: LG¹ and LG² are either both CI or both Br; and

B² is K₂C0₃ or KO'Bu.

31. The process as claimed in any one of Claims 27 to 30, which further comprises the step of preparing the compound of formula Ilia and/or the compound of formula lllb, which step comprises reacting a compound of formula V

R^1a represents X^1a or Y^1a as defined for compounds of formula Ilia or lllb in any preceding claim, as required; and

R^{1 b} represents X^{1 b} or Y^{1 b} as defined for compounds of formula Ilia or lllb in any preceding claim, as required, with a compound of formula VI

R-LG³ (VI) wherein:

R² represents X^2a or Y^2a as defined for compounds of formula Ilia or lllb in any preceding claim, as required; and

LG³ is a suitable leaving group, wherein the reaction is performed in the presence of a suitable base B³ and optionally in the presence of one or more suitable solvents. 32. The process according to Claim 31 , wherein:

LG³ is selected from the group consisting of CI, Br, I, OMs, OTs; and

B³ is selected from the group consisting of K2CO3, Na2C03, CS2CO3, K3PO4, NaOH and KOH.

33. The process according to Claim 31 or Claim 32, wherein: LG³ is Br or I; and

34. The process according to any one of Claims 31 to 33, wherein the steps of the preparing a compound of formula III and preparing a compound of formula II are performed as a one-pot process.

35. A process for the preparation of a compound of formula II , as defined in any of the preceding claims, wherein the process is as defined any one of Claims 27 to 34. 36. A process for the preparation of a compound of formula III, as defined in any of the preceding claims, wherein the process is as defined any one of Claims 31 to 33.

37. A compound of formula I as defined in any of the preceding claims obtainable or obtained using a process as defined in any one of Claims 1 to 34.

38. A compound according to Claim 37, which contains a characteristic impurity, such as a compound of one or more of formulas (a) to (c)

(a) (b) (c) wherein X¹ , X², X³, X⁴, Y¹, Y², Y³, Y⁴, Z and n are as defined in any one of Claims 1 to 8.

39. A compound according to Claim 38, wherein the impurity, or mixture of impurities, is present in an amount of less than 5% by weight.

40. A compound of formula I

or a salt thereof, wherein:

X¹ , X², X³, X⁴, Y\ Y², Y³, Y⁴, Z and n are as defined in any one of Claims 1 to 8, with the proviso that the compounds

salts thereof, are excluded.

41. A compound according to Claim 40, wherein the compound is a compound of formula Ic

or a salt thereof, wherein

X³, X⁴, Y³, Y⁴, Z and n are as defined for compounds of formula I in any one of Claims 1 to 7; and m represents 1 or 2.

42. A compound according to Claim 40 or 41 , wherein X³, X⁴, Y³ and Y⁴ each represent H and n represents 0.

43. A compound according to any one of Claims 40 to 42, wherein m represents 1.

44. A compound according to any one of Claims 40 to 43, wherein the compound is

or a salt thereof.

45. A compound of formula II as defined in any of the preceding claims. 46. The compound according to Claim 45, wherein the compound is a compound of formula lie

wherein X^{1 b} X³ X⁴ Y^{1 b}, Y³, Y⁴, Z and n are as defined in any one of Claims 1 to 8; and p represents 1 or 2.

47. A compound according to Claim 45 or 46, wherein: X^{1 b} and Y^{1 b} each represent Me;

X³, X⁴, Y³ and Y⁴ each represent H; and n represents 0. 48. A compound according to Claim 46 or Claim 47, wherein p represents 1. 49. A process for preparing a catalyst of formula VI I

wherein X¹ , X², X³, X⁴, Y¹ , Y², Y³, Y⁴, Z and n are as defined for compounds of formula I in any preceding claim, which process comprises a reacting a compound of formula I, as defined in any preceding claim, with a suitable source of rhodium, wherein the compound of formula I is prepared using a process according to any one of Claims 1 to 34.

50. A process according to Claim 49, wherein the source of rhodium is R i2(OAc)₄.

51. A catalyst of formula VII

wherein X¹ , X², X³, X⁴, Y¹, Y², Y³, Y⁴, Z and n are as defined in any one of Claims 1 to 7, but with the proviso that the compound

2^Rn2 is excluded.

A catalyst according to Claim 51 , wherein the catalyst is a catalyst of formula VI Ic

wherein X³, X⁴, Y³, Y⁴, Z, m and n are as defined in any one of Claims 1 to 7. A catalyst according to Claim 51 or 52, wherein:

X³, X⁴, Y³ and Y⁴ each represent H; and n represents 0.

A catalyst according Claim 52 or Claim 53, wherein m represents 1.

A catalyst according to any one of Claims 51 to 54, wherein the catalyst i

56. A process for the preparation of a catalyst of formula VII as defined in any one of Claims 51 to 55, wherein the process comprises reacting a corresponding compound of formula I as defined in any one of Claims 40 to 44 with a source of with a suitable source of rhodium.