WO2019025575A1 - Processes for preparing complexes comprising rhodium(ii) and carboxylate ligands - Google Patents

Processes for preparing complexes comprising rhodium(ii) and carboxylate ligands Download PDF

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WO2019025575A1
WO2019025575A1 PCT/EP2018/071086 EP2018071086W WO2019025575A1 WO 2019025575 A1 WO2019025575 A1 WO 2019025575A1 EP 2018071086 W EP2018071086 W EP 2018071086W WO 2019025575 A1 WO2019025575 A1 WO 2019025575A1
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compound
formula
component
reaction
optionally substituted
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PCT/EP2018/071086
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French (fr)
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Abraham MENDOZA
Elisa Martínez DE CASTRO
Samuel Suárez PANTIGA
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Stockholm University Holding Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0073—Rhodium compounds
    • C07F15/008—Rhodium compounds without a metal-carbon linkage

Definitions

  • the present invention relates to new processes for the preparation of metal complexes and to complexes obtained from such processes.
  • it relates to processes for preparing complexes comprising rhodium(ll) and carboxylate ligands, some of which may be useful as catalysts.
  • 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.
  • rhodium(ll) (Rh(ll)) carboxylates have a well-contrasted track record at delivering outstanding catalytic performances (see, for example, Padwa, A. and Austin, D. J., Angewandte Chemie International Edition in English, 33(18), 1797-1815 (1994)). Moreover, they are the only catalyst class that serve distinct processes involving both carbenes and nitrenes. As a result, the original rhodium(ll) catalysts based on simple linear aliphatic carboxylic acids have evolved in the last couple of decades into more intricate ligand designs (see: Espino, C. G. ef a/., J. Am. Chem.
  • One of the 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 hc-roinaft r ac Rh compassioniOcn
  • Rh 2 (esp) 2 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.
  • rhodium(ll) precursors are obtained using reductive processes from the available rhodium(lll) salts, most commonly being RhCb and its hydrates (see: Crombie, A. L. et al., J. Org. Chem., 69(25), 8652-8667 (2004); Winkhaus, G. n. and Ziegler, P., Zeitschrift fur anorganische undwoven Chemie, 350(1-2), 51-61 (1967); Legzdins, P. et al., Journal of the Chemical Society A: Inorganic, Physical, Theoretical, 3322-3326 (1970); Agaskar, P. A. et al., J. Am. Chem.
  • Rh 2 (OAc) 4 one of the most common rhodium(ll) precursors
  • RhCI 3 the rhodium(lll) source
  • Rh 2 (OPiv) 4 Even for the synthesis of one of the simplest rhodium(ll) carboxylates based on a congested carboxylic acid ligand, Rh 2 (OPiv) 4 , the direct synthesis from RhCI 3 is not preparatively useful (4% yield observed in unpublished results, following the procedure in Crombie, A. L. era/., J. Org. Chem., 69(25), 8652-8667 (2004) at footnote 75). As a result, Rh 2 (OPiv) 4 has been normally prepared through a 2-step synthesis via the ligand methathesis on Rh 2 (OAc) 4 (see Kwok, S. W. et al., Angewandte Chemie International Edition, 53, 3452 (2014)).
  • Rh 2 (OAc) 4 rhodium(ll) precursors used in the synthesis of the most advanced catalysts like Na 4 [Rh 2 (C0 3 )4]7 or Rh 2 TFA 4 (TFA, trifluoroacetate) are either prepared from Rh 2 (OAc) 4 (thus adding an extra step in their synthesis) or through similar reduction reactions from RhCI 3 using large excess of reagents (see: Winkhaus, G. n. and Ziegler, P., Zeitschrift fiir anorganische undwoven Chemie, 350(1-2), 51-61 (1967); Agaskar, P. A. et ai, J. Am. Chem. Soc, 108(6), 1214-1223 (1986); Pruchnik, F. P. et al., Inorg. Chim. Acta, 350, 609-616 (2003)). Although some of the yields of these precursors are unreported, none of them is known to be prepared in more than 76% yield (based on RhCb).
  • X represents a ligand comprising one or more carboxylate group; and n represents 1 , 2 or 4, such that the total number of carboxylate groups present in the complex is 4; comprising the step of reacting:
  • complex will take its normal meaning in the art.
  • it may refer to a coordination complex consisting of a central metal atom a surrounding array of bound molecules which may be referred to as ligands.
  • ligand as used herein will take its normal meaning in the art. In particular, it may refer to a molecule that binds to a central metal atom to form a complex.
  • X represents a ligand comprising one or more carboxylate group. As such, the skilled person will understand that it will represent a compound comprising one or more negatively charged carboxylate moiety (i.e. a -C(0)0 " group). In particular, X may represent a compound comprising 1 , 2 or 4 carboxylate moieties. More particularly, X may represent a compound comprising 1 or 2 carboxylate moieties (e.g. 2 carboxylate moieties).
  • n 1 , 2 or 4, such that the total number of carboxylate groups present in the complex is 4.
  • the number of X groups (i.e. ligands) present is sufficient for there to be 4 carboxylate moieties present in the complex.
  • n will represent 2 carboxylate moieties
  • n will represent 2 carboxylate moieties
  • n will represent 1 carboxylate moiety
  • n will represent 4.
  • n 2 or 4.
  • the process of the invention comprises the step of reacting: (a) a source of Rh(III); and (b) a source of X, which may be referred to as components (a) and (b), respectively.
  • the term “reacting” will take its normal meaning in the art. In particular, it may refer to placing the relevant components together in conditions allowing for a reaction (i.e. an interaction resulting in a chemical change) to occur.
  • the term “reacting” may be replaced with the term “bringing together", “adding to a reaction", “adding to a reaction vessel", “allowing to react", or the like.
  • the reaction between the components may proceed through a series of stages involving intermediate (i.e. non-isolated) compounds, and may involve reaction with other reaction components.
  • the reference to reacting components (a) and (b) will refer to the overall effect of the reaction (i.e. bringing components (a) and (b) together such they react to form a product) and may not necessarily imply direct chemical reaction between reaction species as specified.
  • the step of reacting components (a) and (b) may comprise component (a) first reacting to form a non-isolated intermediate compound (or species), which intermediate compound then reacts with components (b), or vice versa.
  • it may comprise first reacting component (a) to form a non-isolated intermediate compound and reacting component (b) to form a non-isolated intermediate compound, which intermediate compounds then react with each other.
  • reaction i.e. the reaction between components (a) and (b)
  • component (c) a suitable reducing agent, which may be referred to as component (c).
  • references herein to a reaction being performed in the presence of a component will refer to such component being present such that it may participate in the reaction.
  • such components may be also be referred to as being “reacted” or brought together with (i.e. by “bringing together") other components of the reaction.
  • the process of the first aspect of the invention may alternatively be referred to as comprising the step of reacting (or the like) components (a), (b) and (c).
  • references to a "suitable reducing agent” will refer to a reducing agent that will effect the necessary reduction as part of the relevant reaction.
  • suitable reducing agents, and amounts required thereof will be well known to those skilled in the art.
  • the reaction as described in the process of the first aspect of the invention is performed under basic conditions, which term will be well understood by those skilled in the art.
  • references to the reaction being performed under basic conditions will refer to the reaction being conducted under conditions wherein substantially all acid groups (e.g. carboxylic acid groups as present in component (b)) are deprotonated (i.e. are ionized or present as corresponding metal salts).
  • references to "substantially all" of a component/substance will refer to an amount that is at least 95% of that component/substance (such as at least 98%, e.g. at least 99% or, particularly, at least 99.9%).
  • references to the reaction being performed under basic conditions may be replaced with references to the reaction being performed under conditions wherein at least 95% of (such as at least 98%, e.g. at least 99% or, particularly, at least 99.9%) of the carboxylic acid groups in component (b) are deprotonated.
  • the source of Rh(lll) i.e. component (a)
  • the source of Rh(lll) is a Rh salt, such as a halide salt.
  • the source of Rh(lll) (component (a)) is RhCI 3 .
  • references herein to salts will include references to such salts in the form of a hydrate thereof (which may be referred to as RhCU.xFfeO).
  • such salts may be present in anhydrous form.
  • the invention encompasses the use of hydrates and anhydrous forms of Rh(lll) salts.
  • the source of X i.e. component (b)
  • the source of X is a carboxy!ic acid and/or salt thereof.
  • the source of X i.e. component (b)
  • is a carboxylic acid i.e. a compound having the required number of carboxylic acid groups
  • references to component (b) being in the form of an acid will refer to the form of component (b) when added to the reaction (i.e. when initially reacted), which form may become altered during the course of the reaction (e.g. by reaction with a base to form an ionized or salt form thereof).
  • reaction in order for the reaction to be performed under basic conditions, the use of a base (as an additional component) may be required.
  • a base as an additional component
  • the reaction is performed in the presence of (d) a suitable base, which may be referred to as component (d).
  • references to a "suitable base” will refer to a base, or combination (i.e. mixture) of bases, the use of which in the reaction (in an appropriate amount) will result in basic reaction conditions, as described herein.
  • suitable bases and amounts thereof will be those the use of which will result in deprotonation of substantially all of the carboxylic acid groups present in component (b).
  • suitable bases may be those having a pKaH of 6 or greater (such as a pKaH of 6.5 or greater, e.g. a pKaH of 7 or greater).
  • the base (component (d)) is selected from the group consisting of: carbonate salts; halide salts; metal hydroxides; and metal hydrides, and mixtures thereof.
  • the base is selected from the group consisting oft alkali metal carbonate salts; alkyl ammonium halides; alkali metal hydroxides; and alkali metal hydrides, and mixtures thereof.
  • alkali metals will refer to metals in Group I of the Periodic Table. In particular, it will refer to Li, Na, K (e.g. Li).
  • the base (component (d)) consists of an alkali metal carbonate salt and/or an alkali metal hydroxide.
  • each cationic component of the base (component (d)) is a lithium cation.
  • Particular bases that may be mentioned include Li carbonate salts and Li hydroxides, and mixtures thereof.
  • the base (component (d)) is selected from the group consisting of Li 2 C03, LiOH, and mixtures thereof.
  • the base (component (d)) is U2CO3 (i.e. lithium carbonate).
  • component (d) an amount of suitable base (component (d)) sufficient to allow for the reaction to be performed under basic conditions.
  • suitable base component (d)
  • such amount may be selected based on the amount required to deprotonate substantially all of the acid moieties present in the reaction (i.e. the carboxylic acid moieties present in component (b)).
  • the molar amount of component (b) per mole of component (d) is less than 1/n (i.e. ( ⁇ 1)/n; e.g. where n is 2, less than 0.5).
  • the molar ratio of component (b) to component (d) is in range (from 0.65 to 0.95) / n : 1.
  • the molar ratio of component (b) to component (d) is about 0.75 / n : 1.
  • component (c) may be a substance that also acts as a suitable solvent.
  • component (c) may be a suitable reductant and solvent (i.e. a compound/substance that is a suitable reductant and solvent).
  • the reducing agent (component (c)) is a suitable solvent (i.e. also acts as a suitable solvent).
  • a suitable reducing agent which may also act as a suitable solvent
  • the reducing agent (component (c)) which may also act as a suitable solvent
  • is an alcohol i.e. a suitable alcohol
  • component (c) may be referred to as a suitable alcohol.
  • Particular such alcohols that may be mentioned include ethanol, methanol, propanol, butanol, pinacol, and ethylene glycol and oligomers thereof.
  • the reducing agent (component (c)) which may also act as a suitable solvent, is ethanol.
  • component (c) may be referred to as ethanol.
  • a suitable amount of component (c) e.g. a suitable amount to act as both reductant and solvent.
  • the process of the first aspect of the invention may be performed in a suitable reaction vessel and, in particular, under a suitable atmosphere (and at a suitable pressure), which may be determined by those skilled in the art.
  • the reaction may be performed under an atmosphere of air (e.g. in an open reaction vessel or a vessel charged with air).
  • the reaction may be performed under other suitable atmospheres, such as atmospheres consisting substantially of 0 2 or Ar, in a suitable reaction vessel (i.e. a closed reaction vessel).
  • the process of the first aspect of the invention may be performed in at a suitable temperature, which may be at or, particularly, greater than room temperature (i.e. about 25 °C).
  • a suitable solvent as described herein; which may serve as component (c)
  • the reaction may be performed at a temperature that is the reflux temperature of that solvent (e.g. the reflux temperature of that solvent under an atmosphere of air in an open reaction vessel equipped with suitable apparatus, such as a reflux condenser).
  • the suitable solvent e.g. as component (c)
  • the reaction may be performed at a temperature that is the reflux point of that solvent (e.g. where the solvent is ethanol, at about 78.3 °C).
  • the process of the first aspect of the invention also allows for preparation of the complex of formula I using lower amounts of carboxylic acid starting material (relative to the source of Rh (III)) than processes of the prior art.
  • the molar ratio of component (a) to component (b) is in the range from 1 : (20/n) to 1 : (2/n).
  • the molar ratio of component (a) to component (b) is in the range from 1 : (5/n) to 1 : (2/n).
  • the process of the first aspect of the invention may allow for the preparation of complexes wherein the ligands are large and sterically congested carboxylate groups (and, therefore, the source of X is a large and sterically congested carboxylic acid or salt thereof, such as a large and sterically congested carboxylic acid).
  • X has a minimum of two carbon atoms, such as wherein X is a C 2 to C 2 o carboxylate. In a more particular embodiment, X is a C 4 to C 20 carboxylate.
  • X comprises one or two carboxylate groups (such that n represents 4 or 2, respectively).
  • X comprises two carboxylate groups (such that n represents 2).
  • component (b) is a compound of formula II
  • X 1 and Y 1 each independently represent C1- 12 alkyl optionally substituted with one or more F
  • X 2 and Y 2 each independently represent C1-12 alkyl, C2-12 alkenyl, 02-12 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 X 1 and X 2 and Y 1 and Y 2 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;
  • X 3 and X 4 each independently represent H or Ch alky! optionally substituted with one or more F;
  • Y 3 and Y 4 each independently represent H or Ci -3 alkyl optionally substituted with one or more F; each Z independently represents halo, Ci -6 alkyl, C2-8 alkenyl or C2-6 alkynyl, wherein the latter three groups are optionally substituted with one or more F; and k represents (an integer from) 0 to 4.
  • the compounds employed in or produced by the processes described herein 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.
  • 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 cycloalkyi 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.
  • particular cycloalkyi groups that may be mentioned include those in which each constituent carbon atom forms part of the ring.
  • 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 (ent ought) 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.
  • 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.
  • aryl when used herein, includes C Pain-io aromatic groups. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, be either wholly or partly aromatic. Particular Ce-10 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.
  • 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.
  • 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 cycloalkyl group that is one ring member larger than another will refer to larger rings containing one more such methylene group within the ring structure. In particular embodiments:
  • X 1 and Y 1 each independently represent Ci -7 alkyl optionally substituted with one or more F
  • X 2 and Y 2 each independently represent Ci- alkyl, Ci-s alkenyl, C 2- 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 and X 2 and Y 1 and Y 2 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.
  • k represents 0.
  • X 1 and Y 1 each independently represent d -3 alkyl optionally substituted by one or more F, and
  • X 2 and Y 2 independently represent Ci-e alkyl, C 2- 5 alkenyl, C 2 -4 alkynyl, phenyl or Ci alkyl- phenyl, optionally substituted with one or more F; or either or both of X 1 and X 2 and Y 1 and Y 2 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.
  • X 1 , X 2 , Y and Y 2 each represent methyl
  • X 1 and X 2 and Y 1 and Y 2 are each joined together to form a 5-membered or 6-membered cycloalkyl.
  • X 1 , X 2 , Y 1 and Y 2 each represent methyl.
  • carboxylic acids and corresponding carboxylate ligands, of interest are those comprising two carboxylic acid groups and having a plane of symmetry positioned between those groups, such that the compounds may be described as being symmetrical.
  • each of X 3 , X 4 , Y 3 and Y 4 represent H.
  • each of X 1 , X 2 , Y 1 and Y 2 represent methyl; each of X 3 , X 4 , Y 3 and Y 4 represent H; and k represents 0.
  • the compound of formula II is a compound of formula Ha
  • X 3 , X 4 , Y 3 , Y 4 , Z and k are as defined herein (i.e. as defined for compounds of formula II in the first aspect of the invention, including all embodiments and combinations of embodiments thereof); and m represents 1 or 2.
  • each of X 3 , X 4 , Y 3 and Y 4 represent H, and k represents 0.
  • component (b) is a compound of the following structure
  • X represents a corresponding carboxylate of the following structure
  • n (as defined for the complex of formula I) represents 2.
  • the step of reacting components (a) and (b) in the process of the first aspect of the invention may be performed as a one pot process.
  • 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 will be performed without purification (for example, by chromatography or distillation) of any intermediate compound prior to completion of the final chemical transformation.
  • the process of the first aspect of the invention further comprises the step of preparing the compound of formula II via a process comprising reacting a corresponding compound of formula III
  • each of X 1a and X 1b represents an X 1 group as defined for compounds of formula II
  • each of Y 1a and Y 1b represents a Y 1 group as defined for compounds of formula II
  • X 2a represents an X 2 group as defined for compounds of formula II
  • Y 2a represents a Y 2 group as defined for compounds of formula II; or either or both of X 1a and X 2a and Y 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 1b and Y 1b each independently represent Ci-12 alkyl optionally substituted with one or more F, wherein the rings formed by X 1a and X 2a and Y a and Y 2a in the compound of formula III are one ring member larger than the rings formed by X 1 and X 2 and Y 1 and Y 2 in the compound of formula II; and
  • X 3 , X 4 , Y 3 , Y 4 , Z and k are as defined for compounds of formula II, wherein the reaction of the compound of formula III to form the compound of formula II is performed in the presence of a source of hydrogen peroxide, and optionally in the presence of a suitable solvent.
  • Suitable salts e.g. of compounds of formula II
  • 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.
  • 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.
  • X 1 and Y 1 each independently represent C alkyl (e.g. Ci -6 alkyl) optionally substituted with one or more F
  • X 2 and Y 2 each independently represent Gi -7 alkyl (e.g. Gi -6 alkyl), C 2 -s alkenyl, 0 2- 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 and X 2 and Y and Y 2 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 1a , X 1b , Y 1a and Y 1b each independently represent Ci-7 alkyl (e.g. Ci -6 alkyl) optionally substituted with one or more F, and
  • X 2a and Y 2a each independently represent Ci -7 alkyl (e.g. C 1-B 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 1a and X 2a and Y 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 and Y 1b each independently represent Ci -6 alkyl optionally substituted with one or more F, wherein the rings formed by X 1a and X 2a and Y 1a and Y a in the compound of formula II are one ring member larger than the rings formed by X 1 and X 2 and Y 1 and Y 2 in the compound of formula I.
  • the X 1 , X 1a , X 1b , Y 1 , Y 1a and Y 1b 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).
  • the X 2 and X a and Y 2 and Y 2a groups may each independently represent Ci-6 alkyl (including C 3 -e cycloalkyl, such as Ci-s alkyl and C 3- 6 cycloalkyl), C 2- 5 alkenyl, C2-4 alkynyl, phenyl or -Ci alkyl-phenyl (i.e. benzyl), optionally substituted with one or more F.
  • Ci-6 alkyl including C 3 -e cycloalkyl, such as Ci-s alkyl and C 3- 6 cycloalkyl
  • C 2- 5 alkenyl C2-4 alkynyl
  • phenyl or -Ci alkyl-phenyl i.e. benzyl
  • the X 2 and X 2a and Y 2 and Y 2a groups may each independently represent Ci -5 linear or branched (e.g. linear) alkyl, Cs-e cycloalkyl, C 2- 4 alkenyl or benzyl, such as linear Ci-5 alkyl, cyclohexyl, -CH 2 -CHCH 2 (i.e. allyl) or benzyl.
  • X 1b and Y 1 in compounds of formula III may represent a group selected from X 1 and Y 1 groups, respectively, as defined for compounds of formula II.
  • the X 1b and Y 1b groups in compounds of formula III are not retained in the compound of formula II.
  • X 1a and Y 1a may correspond to the X 1 and Y 1 groups, respectively, in compounds of formula !!.
  • X 1b and Y b may each independently represent Ci -6 alkyl, such as C1-3 alkyl (e.g. methyl).
  • either or both of X 1 and X 2 and Y 1 and Y 2 in the compound of formula II, and either or both of X 1a and X 2 and Y 1a and Y 2 in the compound of formula III, may be linked to form, together with the atom to which they are attached, a cycloalkyi 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 III are one ring member larger than the rings formed by X 1 and X 2 and Y 1 and Y 2 in the compound of formula II.
  • X b and Y 1b may each independently represent Ci -6 alkyl.
  • X 1b and Y 1 may each independently represent Ci-3 alkyl, such as methyl.
  • X 1 and X 2 and Y 1 and Y 2 in a compound of formula II may be each linked to form a 5-membered cycloalkyi group
  • X 1a and X 2a and Y 1a and Y 2a in a compound of formula III may be each linked to form a 6-membered cycloalkyi group.
  • X 3 , X 4 , Y 3 and Y 4 may each independently represent hydrogen, methyl, ethyl or /so-propyl, such as hydrogen or methyl (e.g. hydrogen).
  • a particular substituent represents hydrogen (i.e. H) the relevant compound may be redrawn without that substituent showing.
  • each Z independently represents halo, Ci-6 alkyl, C2-6 alkenyl or C 2 -6 alkynyl, wherein the latter three groups are optionally substituted with one or more F.
  • each Z may independently represent halo or Ci -3 alkyl, such as bromo, methyl, ethyl or / ' so-propyl (e.g. bromo or methyl, such as methyl).
  • halo or Ci -3 alkyl such as bromo, methyl, ethyl or / ' so-propyl (e.g. bromo or methyl, such as methyl).
  • V1 y1a y1b v1 Via v1b X 2 and X 2a and Y 2 and Y 2a each independently represent Ci -7 alkyl (e.g. Ci-e alkyl), allyl or benzyl; and X 3 , X 4 , Y 3 and Y 4 each represent H.
  • X 1 , X 1a , X 1b , X 2 , X 2a Y 1 , Y a , Y 1b , Y 2 and Y 2a each represent methyl;
  • X 3 , X 4 , Y 3 and Y 4 represent H.
  • X 1 and X 2 and Y 1 and Y 2 are each joined together to form a 5-membered or 6-membered cycloalkyl
  • X 1a and X 2a and Y 1a and Y 2a are each joined together to form a 6-membered or 7-membered cycloalkyl
  • the ring formed by X 1 and X 2 and Y and Y 2 in the compound of formula II 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 III
  • X 1b and Y 1 each represent methyl.
  • X 1 and X 2 and Y 1 and Y 2 are each joined together to form a 5-membered cycloalkyl
  • X 1a and X 2a and Y 1a and Y 2a are each joined together to form a 6-membered cycloalkyl
  • X 1b and Y 1b each represent methyl
  • X b and Y 1 each represent methyl; X 3 , X 4 , Y 3 and Y 4 represent hydrogen; and k represents 0.
  • X and Y 1b each represent methyl
  • X 3 , X 4 , Y 3 and Y 4 represent hydrogen; and k represents 0.
  • X 1 , X 2 , Y and Y 2 each represent methyl; in the compound of formula III, X a , X 2a , Y 1a and Y 2a methyl; X 3 , X 4 , Y 3 and Y 4 represent hydrogen; and k represents 0, more particularly wherein X 1b and Y 1b each represent methyl.
  • Particular compounds of formula II and III include those wherein each corresponding pair of X 1 and Y ⁇ 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 X 1 and X 2 being linked and Y 1 and Y 2 being linked) are the same group.
  • X 1 and Y 1 may represent the same group
  • X 1a and Y 1a may represent the same group
  • X 1b and Y 1 may represent the same group
  • X 2 and Y 2 may represent the same group
  • X 2a and Y 2a may represent the same group
  • X 3 and Y 3 may represent the same group
  • X 4 and Y 4 may represent the same group
  • X 1 and X 2 , Y 1 and Y 2 , 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.
  • X 1 and Y 1 each represent the same C1-12 alkyl group optionally substituted with one or more F;
  • X 2 and Y 2 represent the same group selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl or Ci -3 alkyl-aryl, wherein the latter five groups are optionally substituted with one or more F; or both of X 1 and X 2 and Y 1 and Y 2 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;
  • X 3 and X 4 both represent the same group selected from H or C1-3 alkyl optionally substituted with one or more F; and Y 3 and Y 4 both represent the same group selected from H or C1-3 alkyl optionally substituted with one or more F.
  • X 3 and X 4 both represent the same group selected from H or C1-3 alkyl optionally substituted with one or more F.
  • the X 1 to X 4 and the Y 1 to Y 4 bearing carboxylic acid substituents on the aromatic ring in the compound of formula II and the X 1a to X 4 and the Y a to Y 4 bearing diketone substituents on the aromatic ring in the compound of formula III will be the same.
  • the compounds of formula II and formula III may be symmetrical (i.e. having a plane of symmetry between the carboxylic acid substituents on the central ring in compounds of formula II and III).
  • 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.
  • the compounds of formulae II and III are symmetrical.
  • Z substituents may be positioned at the 2, 4, 5 and 6 positions of the benzene ring (as numbered with respect to the X 1 to X 4 and Y 1 to Y 4 substituted carboxylic acid groups, numbered sequentially from the Y 1 to Y 4 substituted carboxylic acid group bearing carbon atom in the anticlockwise direction as depicted), and such groups may be referred to as Z 1 , Z 2 , Z 3 and Z 4 , respectively.
  • the compound of formula II is a compound of formula lib
  • X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , ⁇ 3 and ⁇ 4 are as defined herein (i.e. for compounds of formula II, or any embodiment or combination of embodiments thereof); and Z 1 , Z 2 , Z 3 and Z 4 independently represent a group selected from Z, as defined herein, or H.
  • Z 1 represents H, halo or Ci -3 alkyl; and Z 2 , Z 3 and Z 4 independently represent halo, Ci-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, wherein the latter three groups are optionally substituted with one or more F.
  • Z 1 represents H; and/or (e.g. and)
  • Z 2 , Z 3 and Z 4 each independently represent halo, Ci -3 alkyl, C 2- 3 alkenyl or C 2- 3 alkynyl, wherein the latter three groups are optionally substituted with one or more F.
  • Z 2 , Z 3 and Z 4 each independently represent halo, Ci -3 alkyl, C 2- 3 alkenyl or C 2- 3 alkynyl, wherein the latter three groups are optionally substituted with one or more F.
  • Z 1 and Z 3 independently represent halo or H
  • Z 2 and Z 4 represent H.
  • Z 1 and Z 3 independently represent Br or H; and Z 2 and Z 4 represent H.
  • Z 1 , Z 2 and Z 4 represent H; and Z 3 represents Br.
  • Z 1 , Z 2 and Z 4 each represent Me; and Z 3 represents H.
  • Z 1 to Z 4 each represent H.
  • the compound of formula II is a compound of formula lie
  • the compound for formula II may be a compound of formula lla.
  • the compound of formula III may be a compound of formula Ilia
  • X 1b , X 3 , X 4 , Y 1b , Y 3 , Y 4 and k are as defined herein (i.e. for compounds of formula II, including all embodiments and combinations of embodiments thereof), and m' represents m + 1.
  • the compound of formula III will be a compound of formula wherein X 1b and Y 1b are as defined herein (i.e. for compounds of formula III, including all embodiments and combinations of embodiments thereof).
  • the process for preparing the compound of formula II may be facilitated by the addition of a suitable base, which may have a catalytic effect.
  • a suitable base which may have a catalytic effect.
  • the reaction for preparing the compound of formula II is optionally performed in the presence of a suitable base B 1 .
  • the reaction for preparing the compound of formula II is performed in the presence of a suitable base B 1 .
  • Suitable bases that may be employed as B 1 in the process for preparing the compound of formula II include inorganic bases (such as, metal carbonates, metal hydroxides, metal alkoxides and metal oxides).
  • the suitable base B 1 is a metal hydroxide, a metal alkoxide or a metal oxide.
  • the suitable base B 1 is selected from the group consisting of LiOH, LiOMe, LiOEt, LiO'Bu NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt and KO3 ⁇ 4u, CaO, MgO and Al 2 0 3 (i.e. alumina; in particular, basic alumina).
  • the suitable base B 1 is NaOH (i.e. sodium hydroxide) or LiOH (i.e. lithium hydroxide). Most preferably, the suitable base B 1 is NaOH.
  • the process for preparing the compound of formula II may be facilitated by the addition of a suitable acid, which may have a catalytic effect.
  • the reaction for preparing the compound of formula II may optionally be performed in the presence of a suitable acid A 1 .
  • the reaction for preparing the compound of formula II is performed in the presence of a suitable acid A 1 .
  • the suitable acid A 1 may be a mineral acid (such as, HCI, H 2 S0 4 , HN0 3 or H3PO4) or, more particularly, an organic acid (such as, acetic acid, trifluoroacetic acid, camphor sulfonic acid or para-toluenesulfonic acid).
  • the acid A 1 is an organic acid.
  • the acid A 1 is a carboxylic acid or a sulfonic acid.
  • the acid A 1 is acetic acid, trifluoroacetic acid, camphor sulfonic acid or para-toluenesulfonic acid.
  • an acidic or basic additive and/or catalyst is not essential to the process for preparing the compound of formula II, 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).
  • Suitable sources of hydrogen peroxide 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).
  • concentrations for example, in concentrations ranging from 20% to 70% by weight, preferably 20% to 50% by weight.
  • concentrations for example, in concentrations ranging from 20% to 70% by weight, preferably 20% to 50% by weight.
  • a particular source of hydrogen peroxide that may be mentioned is 30% by weight aqueous hydrogen peroxide solution.
  • the source of hydrogen peroxide is aqueous hydrogen peroxide.
  • the process for preparing the compound of formula II may be performed with a range of equivalents of hydrogen peroxide with respect to (i.e. relative to) the compound of formula III.
  • 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 III, such as from about 2 to about 6 equivalents (e.g. from about 3 to about 5 equivalents; in particular, about 4 equivalents).
  • the process for preparing the compound of formula II 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 III.
  • 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).
  • 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.
  • the term “about” may be omitted throughout.
  • the process for preparing the compound of formula II may be performed in the presence of a suitable solvent.
  • 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).
  • the process may also be performed in the absence of an additional suitable solvents.
  • the process for preparing the compound of formula II 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.
  • the suitable solvent is a protic solvent.
  • the suitable solvent is an aprotic solvent.
  • 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.
  • an aprotic solvent particular solvents that may be mentioned include dichloromethane, dimethylsulfoxide, ⁇ ,/V-dimethylformamide and 1',1 ',1'-trifluorotoluene, and mixtures thereof.
  • suitable temperatures include those from about 0 °C to about 100 °C.
  • the process for preparing the compound of formula II may be performed at temperatures from about 0 °C to room temperature.
  • the skilled person will appreciate that it may be preferable to vary the temperature of the reaction vessel used for the process for preparing the compound of formula II at different points to control the reaction rate; for example, during the addition of highly reactive chemical species.
  • 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.
  • 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, within about 5 °C) of 0 °C.
  • room temperature may be understood to mean the ambient temperature of the room.
  • 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.
  • 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).
  • reaction conditions include performing the process at temperatures from about 0 °C to about 25 °C in the presence of methanol.
  • reaction conditions 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 A 1 or B ).
  • the process of the first aspect of the invention which further comprises the step of preparing the compound of formula III as defined hereinabove, which step comprises reacting a compound of formula IVa
  • X 3 , X 4 , Y 3 and Y 4 , Z and k are as defined hereinabove (including wherein Z is represented as Z 1 to Z 4 , as described herein above); and
  • LG 1 and LG 2 each independently represent a suitable leaving group, wherein the reaction (to prepare the compound of formula III) is performed in the presence of a suitable base B 2 , and optionally in the presence of one or more suitable solvents.
  • the step of preparing a compound of formula III as defined hereinabove comprises reacting a compound of formula IVa and a compound of formula IVb with a compound of formula Va
  • the step of preparing a compound of formula III as defined hereinabove comprises reacting a compound of formula IVa and a compound of formula IVb with a compound of formula Vb
  • LG 1 and LG 2 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).
  • halo e.g. CI or Br
  • S-alkyl/S-aryl sulphonates e.g. OMs, OTs, OBr, ONs, such as OMs and OTs.
  • LG 1 and LG 2 are independently selected from CI and Br.
  • LG 1 and LG 2 may be the same group.
  • the suitable base B 2 may be a metal carbonate, metal hydroxide, metal alkoxide or metal oxide.
  • B 2 may be selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 , NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt, KOSu, CaO, MgO and Al 2 0 3 (in particular, basic alumina).
  • B 2 may be selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 and KO'Bu (e.g. KO3 ⁇ 4u or K 2 C0 3 ).
  • LG 1 and LG 2 are each independently selected from the group consisting of CI, Br, I, OMs and OTs; and/or (e.g. and)
  • B 2 is selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 , NaOH, KOH and KO3 ⁇ 4u.
  • K 2 C0 3 Na 2 C0 3
  • LG 1 and LG 2 are either both CI or both Br; and/or (e.g. and)
  • the step of the preparation of a compound of formula III may be performed in the presence of an additive, which additive may serve to promote the reaction.
  • additives which additive may serve to promote the reaction.
  • Kl i.e. potassium iodide
  • 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.
  • solvents that may be mentioned (i.e. for the process for preparing the compound of formula III) 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).
  • 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
  • ketones e.g. acetone
  • Particular solvents that may be mentioned are i-butanol and 1 ,2-dimethoxy ethane.
  • Particularly preferred conditions for the step of the preparation of a compound of formula III involve heating to reflux (i.e. around 85 °C) in 1 ,2-dimethoxyethane.
  • 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.
  • the step of preparing a compound of formula iii is performed with at least one equivalent of the compound of formula IVa and at least one equivalent of the compound of formula IVb with respect to the compound of formula V.
  • 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.
  • the step of preparing a compound of formula III is performed with at least two equivalents of the diketone compound (i.e. the compound of formula IVa and IVb) with respect to the compound of formula V.
  • 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.
  • the process of the invention comprising the step of preparing a compound of formula III, which further comprises the step(s) of preparing the compound of formula IVa and/or (e.g. and) the compound of formula IVb, which step(s) comprise(s) reacting a compound of formula VI wherein:
  • R 1a represents X 1a or Y 1a as hereinabove defined, as required; and R 1 represents X 1b or Y 1 as hereinabove defined, as required, with a compound of formula VII R 2 -LG 3 (vii) wherein:
  • R 2 represents X 2a or Y 2a as hereinabove defined, as required;
  • LG 3 is a suitable leaving group, wherein the reaction is performed in the presence of a suitable base B 3 , and optionally in the presence a suitable solvent.
  • LG 3 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).
  • LG 3 is selected from the group consisting of CI, Br, I, OMs and OTs (e.g. Br or I).
  • the suitable base B 3 may be a metal carbonate, metal hydroxide, metal alkoxide or metal oxide.
  • B 3 is selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 , NaOH, NaOMe, NaOEt, NaO'Bu, KOH, KOMe, KOEt and KO'Bu, CaO, MgO or Al 2 0 3 (in particular basic alumina).
  • B 3 is selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 K 3 P0 4 , NaOH and KOH (e.g. K 2 C0 3 ).
  • LG 3 is selected from the group consisting of CI, Br, I, OMs, OTs; and/or (e.g. and)
  • B 3 is selected from the group consisting of K 2 C0 3 , Na 2 C0 3 , Cs 2 C0 3 , K 3 P0 , NaOH and KOH.
  • LG 3 is Br or I
  • B 3 is K 2 C0 3 .
  • the step of the preparation of a compound of formula IVa and/or (e.g. and) IVb 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.
  • solvents that may be mentioned include alcohols (e.g. methanol, ethanol, /-propanol or f-butanol), ethers (e.g. methyl i-butyl ether or 1 ,2-dimethoxy ethane), chlorinated hydrocarbons (e.g. dichloromethane), and ketones (e.g. acetone).
  • alcohols e.g. methanol, ethanol, /-propanol or f-butanol
  • ethers e.g. methyl i-butyl ether or 1 ,2-dimethoxy ethane
  • chlorinated hydrocarbons e.g. dichloromethane
  • ketones e.g. acetone
  • Particularly preferred conditions for the step of the preparation of a compound of formula Iva or IVb involve heating under reflux conditions in acetone (e.g. at around 56 °C).
  • the compound of formula IVa and/or (e.g. and) IVb may be formed in situ (e.g. in relation to the subsequent formation of the compound of formula II).
  • the steps of the preparing a compound of formula IVa and/or (e.g. and) IVb and preparing a compound of formula III are performed as a one pot process.
  • the steps of preparing a compound of formula IVa and/or e.g.
  • IVb and a compound of formula II is a one-pot process, a particular such process may comprise; i) heating a compound of VI and a compound of formula VII in the presence of a suitable base (e.g. K 2 C0 3 ) and a suitable solvent (e.g. acetone) at reflux and allowing the reaction to cool to room temperature; and
  • a suitable base e.g. K 2 C0 3
  • a suitable solvent e.g. acetone
  • Particular compounds of formula II and (corresponding) compounds of formula III that may be mentioned include those of the examples as provided hereinbelow.
  • particular (corresponding) compounds of formulas Iva, IVb, V, VI and VII that may be mentioned include those of the examples as provided hereinbelow.
  • particular processes of the first aspect of the invention that may be mentioned include those of the examples as provided hereinbelow.
  • complexes of formula I prepared using the process of the first aspect of the invention may have characteristic features that would distinguish such complexes over complexes prepared using processes as described in the prior art.
  • a complex of formula I, as defined herein obtainable or obtained using the process of the first aspect of the invention (including all embodiments and combinations of embodiments thereof).
  • compounds of formula II prepared using the process for the preparation of compounds of formula II as described herein may comprise characteristic impurities resulting from the process used for their preparation, which impurities may also be present in complexes of formula I.
  • such characteristic impurities may be one or more of: a compound of one or more of formulas (a) to (c)
  • the complex of formula I may comprise, 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.
  • the characteristic impurity may be a by-product (i.e. a side product) resulting from the process for preparing the compound of formula III and/or the product of reacting a by-product resulting from the process for preparing the compound of formula III in the process for preparing a compound of formula II.
  • a by-product i.e. a side product
  • the by-product i.e. a side product
  • the by-product i.e. a side product
  • the product of reacting a by-product resulting from the process for preparing the compound of formula III in the process for preparing a compound of formula II may be one or more of the compounds shown in Table 1 below.
  • the characteristic impurity, or mixture of such impurities may be present in an amount of less than 5% (e.g. less than 1 %) by weight of a sample of the complex of formula I.
  • the process of the first aspect 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.
  • the process of the invention may allow for the direct synthesis of commercially important complexes (including catalysts used in synthetic processes) from readily available starting materials (e.g. Rh(lll) salts), and using lower amounts of certain starting materials (e.g. carboxylic acid ligands) than processes of the prior art, thus allowing for a more cost-efficient manufacturing process.
  • Figure 1 illustrates the comparative catalytic activities of Rh 2 (cpesp)2 and Rh 2 (esp)2 in a C-H amination process as described in Example 19 herein below.
  • Figure 1 shows that the use of Rh 2 (cpesp) 2 resulted in improved yields (as determined by 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 4. E am les
  • 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).
  • reaction mixture When specified, the reaction mixture was immersed in an ultrasonic bath Badeiin Sonorex Digitex.
  • Buchi stirred autoclave bep 280 equipped with a 20 L steel pressure vessel type 3 was used.
  • Example 1a Synthesis of rhodium (II) trimethylacetate dimer (Rh 2 (Piv)4) (50 mq scale) U2CO3 (53 mg, 0.718 mmols, 3.7 equiv.) and pivalic acid (55.5 mg, 0.543 mmols, 2.8 equiv.) were suspended in ethanol (99.5%, 10 mL), in a 20 mL pressure tube. Rhodium chloride hydrate (81.2 % wt, 50 mg, 0.194 mmols) was added and the suspension was stirred at room temperature for 30 min and then heated up to 90°C (aluminium block temperature) for 4 hours.
  • Rhodium chloride hydrate 81.2 % wt, 50 mg, 0.194 mmols
  • ethanol 99.5%, 50 mL
  • Rhodium chloride hydrate (81.2 % wt, 250 mg, 0.970 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then, heated up gradually to 80 ° C (silicone bath temperature) using the following temperature ramp: r.t to 50 ° C (2 ° C/min), 10 min at 50 degrees, 50 ° C to 60 ° C (2 ° C/min), 1 hour at 60 ° C, 60 * C to 70 ° C (2 " C/min), 30 min at 70 ° C, 70°C to 80 ° C (2 ' C/min), 2.5 hours at 80 ° C.
  • Li 2 C0 3 (108 mg, 1.455 mmols, 3 equiv.) and triphenylacetic acid (280 mg, 0.97 mmols, 2 equiv.) were suspended in ethanol (99.5%, 25mL) in a 50 mL round bottom flask equipped with a reflux condenser.
  • Rhodium chloride hydrate (81.2 % wt, 125 mg, 0.485 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then heated up gradually to 80 ° C (silicone bath temperature) using the following temperature ramp: r.t to 50 ° C (2 ° C/min), 10 min at 50 degrees, 50 ° C to 60 ° C (2 ° C/min), 1 hour at 60 ° C, 60 to 70 ° C (2 ' C/min), 30 min at 70 , 70 to 80 ° C (2 ° C/min), 2 hours at 80 ° C.
  • L12CO3 222 mg, 3.01 mmols, 3.1 equiv.
  • ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethyl-l ,3-benzenedipropionic acid 270 mg, 0.970 mmols, 1.0 equiv.
  • Rhodium chloride hydrate (81.2 % wt, 250 mg, 0.970 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then, heated up to 80 ° C (silicone bath temperature) using the following temperature ramp: r.t to 50 ° C (2 ° C/min), 10 min at 50 degrees, 50 ° C to 60 ° C (2 ° C/min), 1 hour at 60 ° C, 60 " C to 70 ° C (2 ° C/min), 30 min at 70 ° C, 70 ° C to 80 ° C (2 ° C/min), 2.5 hours at 80 ° C. The colour of the suspension was changing from deep red to brown and finally green.
  • Example 4 Screening of reaction conditions RhCI 3 hydrate (81.2% wt, 5 mg, 0.0194 mmols), the appropriate carboxylic acid ligand (in the amounts indicated), and the base (in the amounts indicated), were suspended in EtOH (99.5%, 1 mL) in a closed vial and stirred at room temperature for 30 min under air (unless indicated otherwise). Then, the vial was warmed to 90 D C (aluminium block temperature) for 4 hours (unless indicated otherwise).
  • 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 K 2 CO3 (3.73 g, 27 mmol, 2.7 equiv.). After 5 min under vigorous stirring (400 rpm), Me! (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 ⁇ , ⁇ '-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 K 2 C0 3 (3.73 g, 27 mmol, 2.7 equiv.).
  • 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%).
  • 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.
  • Step 1 Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-acetylcyclohexan-1-one) (CpespH 2 ; Compound 3)
  • 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).
  • Step 2 1, 1'-(1,3-phenylenebis(methylene))dicyclopentanecarboxylic acid (cpespH 2 ; Compound 4)
  • 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).
  • 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).
  • pentane-2, 4-dione (3.00 g, 30.0 mmol
  • acetone 30 ml
  • potassium carbonate 4.15 g, 30.0 mmol
  • the mixture was allowed to stir at 400 rpm for 5 min.
  • 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.
  • 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).
  • pentane-2,4-dione 1.502 g, 15.00 mmol
  • acetone 15.00 ml
  • freshly powdered potassium carbonate 2.073 g, 15.00 mmol
  • 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.
  • 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).
  • pentane-2,4-dione 1.502 g, 15.00 mmol
  • acetone 15.00 ml
  • freshly powdered potassium carbonate 2.073 g, 15.00 mmol
  • the mixture was allowed to stir at 400 rpm for 5 min.
  • (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.
  • 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 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 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 HCI 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high- vacuum line.
  • 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).
  • pentane-2,4-dione 2.403 g, 24.00 mmol
  • acetone (12.00 ml)
  • freshly powdered potassium carbonate 3.32 g, 24.00 mmol
  • the mixture was allowed to stir at 400 rpm for 5 min.
  • 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.
  • 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 HC1 1 M (2 x 20 ml), dried over sodium sulfate, filtered and concentrated in rotavapor and high- vacuum line (1 day at 40°C).
  • 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).
  • pentane-2,4-dione 2.403 g, 24.00 mmol
  • Acetone (12.00 ml)
  • freshly powdered potassium carbonate 3.32 g, 24.00 mmol
  • the mixture was allowed to stir at 400 rpm for 5 min.
  • 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.
  • 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).
  • 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 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.
  • 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 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.
  • 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.
  • 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 ethenethyl acetate (1:1) (20 ml).
  • t e mixture was cooled down tu 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.
  • 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.
  • ⁇ ⁇ ic uuian icu ⁇ 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 mixture was cooled to room temperature and diluted with methyl terf-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 ferf-butyl ether (2 x 1.5 L).
  • the precipitate formed in the filtrate was filtered off and washed with methyl terf-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-%.
  • 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.
  • Rh 2 (cpesp) 2 The catalytic activity of Rh 2 (cpesp) 2 , at a range of catalytic loadings, was compared against the standard commercially available Rh 2 (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.
  • 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 mol, 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 CH 2 CI 2 (4 mL), and filtered through a pad of Celite (20 x 7 mm). The filter cake was rinsed with CH 2 CI 2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by 1 H-NMR (CDCI 3 ) using 1 ,1 ,2,2-tetrachloroethane as internal standard.
  • 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 mol, 0.05 mol%; 0.0025 M in anhydrous DCM). The resulting mixture was allowed to stir at room temperature (12 h).
  • 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 pmol, 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 CH2CI 2 (4 mL), and filtered through a pad of Celite (20 x 7 mm).
  • 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. 10 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 pmol, 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 CH 2 CI 2 (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by 1 H-NMR (CDCI 3 ) using 1 ,1 ,2,2-tetrachloroethane as internal standard.
  • Rh 2 (cpesp) 2 resulted in improved yields at all catalyst loadings, indicating improved catalytic turnover. The effect was particularly apparent at lower catalyst loadings.
  • Table 4 A summary of the comparative catalytic activity observed is provided in Table 4 below and illustrated graphically in Figure 1,
  • Rh 2 (esp) 2 0.15% 18% 82%
  • Rh 2 (cpesp) 2 0.15% 41 % 58%
  • Rh 2 (esp) 2 0.05% 5% 90%
  • Rh 2 (cpesp) 2 0.05% 23% 67%

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Abstract

There is provided herein a process for the preparation of a complex of formula (I): Rh(II)2 Xn, wherein X and n have meanings provided in the description, comprising the step of reacting: (a) a source of Rh(III); and (b) a source of X, wherein the reaction is performed in the presence of: (c) a suitable reducing agent, and wherein the reaction is performed under basic conditions.

Description

PROCESSES FOR PREPARING COMPLEXES COMPRISING RHODIUM(II) AND CARBOXYLATE LIGANDS
Field of the Invention
The present invention relates to new processes for the preparation of metal complexes and to complexes obtained from such processes. In particular, it relates to processes for preparing complexes comprising rhodium(ll) and carboxylate ligands, some of which may be useful as catalysts.
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 various catalysts available for insertion reactions, rhodium(ll) (Rh(ll)) carboxylates have a well-contrasted track record at delivering outstanding catalytic performances (see, for example, Padwa, A. and Austin, D. J., Angewandte Chemie International Edition in English, 33(18), 1797-1815 (1994)). Moreover, they are the only catalyst class that serve distinct processes involving both carbenes and nitrenes. As a result, the original rhodium(ll) catalysts based on simple linear aliphatic carboxylic acids have evolved in the last couple of decades into more intricate ligand designs (see: Espino, C. G. ef a/., J. Am. Chem. Soc, 126 (47), 15378-15379 (2004); and Liao, K. et a/., Nature, 533(7602), 230-234 (2016)). Particularly, monodentate and bidentate all-carbon quaternary carboxylates have delivered the highest catalytic activity and the best stability in the aggressive conditions required for the hard functionalizations that they enable and regulate.
One of the 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 hc-roinaft r ac Rh„iOcn
Figure imgf000004_0001
(wherein "esp" represents a, a, a',a'-tetramethyl-1 ,3-benzenedipropionate). Rh2(esp)2 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.
Despite their utility, the production of their rhodium(ll) complexes is still limited by the need to perform challenging ligand metathesis reactions utilizing expensive rhodium(ll) precursors (see: ibid; Hashimoto, S. et al., Tetrahedron Lett., 33(19), 2709-2712 (1992); Callot, H. J. and Metz, F., Tetrahedron, 41(20), 4495-4501 (1985); Kornecki, K. P. and Berry, J. F., Eur. J. Inorg. Chem., 2012(3), 562-568 (2012); and Roos, G. H. P. and McKervey, Synth. Commun., 22(12), 1751-1756 (1992)). At present, such rhodium(ll) precursors are obtained using reductive processes from the available rhodium(lll) salts, most commonly being RhCb and its hydrates (see: Crombie, A. L. et al., J. Org. Chem., 69(25), 8652-8667 (2004); Winkhaus, G. n. and Ziegler, P., Zeitschrift fur anorganische und allgemeine Chemie, 350(1-2), 51-61 (1967); Legzdins, P. et al., Journal of the Chemical Society A: Inorganic, Physical, Theoretical, 3322-3326 (1970); Agaskar, P. A. et al., J. Am. Chem. Soc, 108(6), 1214-1223 (1986); Pruchnik, F. P. et al., Inorg. Chim. Acta, 350, 609-616 (2003); Johnson, S. A. et al., Inorg. Chem., 2(5), 960-962 (1963); Stephenson, T. A. et al., Journal of the Chemical Society (Resumed), 3632-3640 (1965)).
This multi-step sequence has served well the discovery of venerable catalysts such as Rh2(esp)2 but it is at the moment the origin of a large production cost, which limits its applicability by the chemical community at large. Direct translation of the conditions used to obtain simpler rhodium(ll) precursors are impractical using elaborate ligand structures, due to the large excess of carboxylate ligands required and the over-reduction and aggregation problems during the formation of the rhodium(ll) compounds. Notably, it is believed that all of the reported synthesis of rhodium(ll) carboxylates from RhCI3 are performed in acidic media. For example, the synthesis of Rh2(OAc)4 (one of the most common rhodium(ll) precursors) involves the reduction of the rhodium(lll) source (RhCI3) using ethanol as both solvent and reductant in the presence of 90 equiv. of AcOH and 4 equiv. of NaOAc (Legzdins, P. et al. Journal of the Chemical Society A: Inorganic, Physical, Theoretical, 3322-3326 (1970)). Even for the synthesis of one of the simplest rhodium(ll) carboxylates based on a congested carboxylic acid ligand, Rh2(OPiv)4, the direct synthesis from RhCI3 is not preparatively useful (4% yield observed in unpublished results, following the procedure in Crombie, A. L. era/., J. Org. Chem., 69(25), 8652-8667 (2004) at footnote 75). As a result, Rh2(OPiv)4 has been normally prepared through a 2-step synthesis via the ligand methathesis on Rh2(OAc)4 (see Kwok, S. W. et al., Angewandte Chemie International Edition, 53, 3452 (2014)).
Other common rhodium(ll) precursors used in the synthesis of the most advanced catalysts like Na4[Rh2(C03)4]7 or Rh2TFA4 (TFA, trifluoroacetate) are either prepared from Rh2(OAc)4 (thus adding an extra step in their synthesis) or through similar reduction reactions from RhCI3 using large excess of reagents (see: Winkhaus, G. n. and Ziegler, P., Zeitschrift fiir anorganische und allgemeine Chemie, 350(1-2), 51-61 (1967); Agaskar, P. A. et ai, J. Am. Chem. Soc, 108(6), 1214-1223 (1986); Pruchnik, F. P. et al., Inorg. Chim. Acta, 350, 609-616 (2003)). Although some of the yields of these precursors are unreported, none of them is known to be prepared in more than 76% yield (based on RhCb).
Thus, there exists a clear and unmet need for an effective preparation of rhodium(ll) carboxylates directly (i.e. in a single reaction) from cheap and readily available precursors, such as RhCI3, under commercially viable reaction conditions. Perhaps surprisingly given its relatively simple and symmetrical structure, the synthesis of the espH2 ligand also 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 espH2 having been reported.
The established, and to the best of our knowledge only, route reported for the synthesis of espH2 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: Espino er a/., J. Am. Chem. Soc, 126, 15378-15379 (2004); and Kornecki et al. Chem. Comm., 48, 12097 (2012)). 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 organometallics.
Thus, there is also a need for an alternative process for the synthesis of complex carboxylate ligands, such as espH2, 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. Moreover, the ability to synthesis such ligands using less harsh conditions may also allow for the preparation of previously inaccessible ligands.
Disclosure of the Invention
We have now surprisingly found a mild and scalable process that allows highly efficient, direct access to rhodium(ll) carboxylate complexes, which is of particular use in the preparation of complexes comprising sterically congested dicarboxylate ligands.
In a first aspect of the invention, there is provided a process for the preparation of a complex of formula I Rh(ll)2 Xn (I) wherein:
X represents a ligand comprising one or more carboxylate group; and n represents 1 , 2 or 4, such that the total number of carboxylate groups present in the complex is 4; comprising the step of reacting:
(a) a source of Rh(lll); and
(b) a source of X, wherein the reaction is performed in the presence of: (c) a suitable reducing agent, and wherein the reaction is performed under basic conditions, which process may be referred to herein as the process of the first aspect of the invention.
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.
As used herein (i.e. in the first aspect of the invention), in the process of the first aspect of the invention the term "complex" will take its normal meaning in the art. In particular, it may refer to a coordination complex consisting of a central metal atom a surrounding array of bound molecules which may be referred to as ligands.
As such, the term "ligand" as used herein will take its normal meaning in the art. In particular, it may refer to a molecule that binds to a central metal atom to form a complex.
As described herein, X represents a ligand comprising one or more carboxylate group. As such, the skilled person will understand that it will represent a compound comprising one or more negatively charged carboxylate moiety (i.e. a -C(0)0" group). In particular, X may represent a compound comprising 1 , 2 or 4 carboxylate moieties. More particularly, X may represent a compound comprising 1 or 2 carboxylate moieties (e.g. 2 carboxylate moieties).
As described herein, n represents 1 , 2 or 4, such that the total number of carboxylate groups present in the complex is 4. Thus, in the complex of formula I the number of X groups (i.e. ligands) present is sufficient for there to be 4 carboxylate moieties present in the complex. For example, where each X comprises 2 carboxylate moieties, n will represent 2, such that there are four carboxylate moieties present in the complex. Similarly, where each X comprises 1 carboxylate moiety, n will represent 4.
In particular embodiments, n represents 2 or 4. For example, n may represent 2. As described herein, the process of the invention comprises the step of reacting: (a) a source of Rh(III); and (b) a source of X, which may be referred to as components (a) and (b), respectively. As used herein, the term "reacting" will take its normal meaning in the art. In particular, it may refer to placing the relevant components together in conditions allowing for a reaction (i.e. an interaction resulting in a chemical change) to occur. As such, in the context of the process of the first aspect of the invention, the term "reacting" may be replaced with the term "bringing together", "adding to a reaction", "adding to a reaction vessel", "allowing to react", or the like.
For the avoidance of doubt, the skilled person will understand that the reaction between the components (i.e. between components (a) and (b)) may proceed through a series of stages involving intermediate (i.e. non-isolated) compounds, and may involve reaction with other reaction components. As such, the reference to reacting components (a) and (b) will refer to the overall effect of the reaction (i.e. bringing components (a) and (b) together such they react to form a product) and may not necessarily imply direct chemical reaction between reaction species as specified. For example, the step of reacting components (a) and (b) may comprise component (a) first reacting to form a non-isolated intermediate compound (or species), which intermediate compound then reacts with components (b), or vice versa. Similarly, it may comprise first reacting component (a) to form a non-isolated intermediate compound and reacting component (b) to form a non-isolated intermediate compound, which intermediate compounds then react with each other.
As described herein, the reaction (i.e. the reaction between components (a) and (b)) is performed in the presence of (c) a suitable reducing agent, which may be referred to as component (c).
For the avoidance of doubt, references herein to a reaction being performed in the presence of a component (e.g. the reaction of the first aspect of the invention being performed in the presence of component (c)) will refer to such component being present such that it may participate in the reaction. As such, such components may be also be referred to as being "reacted" or brought together with (i.e. by "bringing together") other components of the reaction. For example, the process of the first aspect of the invention may alternatively be referred to as comprising the step of reacting (or the like) components (a), (b) and (c).
As used herein, references to a "suitable reducing agent" will refer to a reducing agent that will effect the necessary reduction as part of the relevant reaction. For example, in relation to component (c) as employed in the process of the first aspect of the reaction will refer to a reducing agent suitable for (i.e. that will effect) reduction of the Rh(lll) species (of component (a)) to provide a Rh(ll) species (as comprised in the complex as formed in the process of the first aspect of the invention). Such suitable reducing agents, and amounts required thereof, will be well known to those skilled in the art.
As described herein, the reaction as described in the process of the first aspect of the invention is performed under basic conditions, which term will be well understood by those skilled in the art. In particular, references to the reaction being performed under basic conditions will refer to the reaction being conducted under conditions wherein substantially all acid groups (e.g. carboxylic acid groups as present in component (b)) are deprotonated (i.e. are ionized or present as corresponding metal salts).
As used herein, references to "substantially all" of a component/substance will refer to an amount that is at least 95% of that component/substance (such as at least 98%, e.g. at least 99% or, particularly, at least 99.9%).
Thus, references to the reaction being performed under basic conditions may be replaced with references to the reaction being performed under conditions wherein at least 95% of (such as at least 98%, e.g. at least 99% or, particularly, at least 99.9%) of the carboxylic acid groups in component (b) are deprotonated.
In a particular embodiment (i.e. a particular embodiment of the first aspect of the invention), the source of Rh(lll) (i.e. component (a)) is a Rh salt, such as a halide salt. In a more particular embodiment, the source of Rh(lll) (component (a)) is RhCI3.
For the avoidance of doubt, references herein to salts (such as Rh salts, e.g. RhCI3) will include references to such salts in the form of a hydrate thereof (which may be referred to as RhCU.xFfeO). Similarly, such salts may be present in anhydrous form. For the avoidance of doubt, the invention encompasses the use of hydrates and anhydrous forms of Rh(lll) salts. In a particular embodiment, the source of X (i.e. component (b)) is a carboxy!ic acid and/or salt thereof. In a more particular embodiment, the source of X (i.e. component (b)) is a carboxylic acid (i.e. a compound having the required number of carboxylic acid groups) that is not in salt form.
For the avoidance of doubt, the skilled person will understand that references to component (b) being in the form of an acid (i.e. in non-salt form) will refer to the form of component (b) when added to the reaction (i.e. when initially reacted), which form may become altered during the course of the reaction (e.g. by reaction with a base to form an ionized or salt form thereof).
The skilled person will understand that, in order for the reaction to be performed under basic conditions, the use of a base (as an additional component) may be required. Thus, in a particular embodiment, the reaction is performed in the presence of (d) a suitable base, which may be referred to as component (d).
As used herein, references to a "suitable base" will refer to a base, or combination (i.e. mixture) of bases, the use of which in the reaction (in an appropriate amount) will result in basic reaction conditions, as described herein. Thus, such suitable bases (and amounts thereof) will be those the use of which will result in deprotonation of substantially all of the carboxylic acid groups present in component (b). In particular, such suitable bases may be those having a pKaH of 6 or greater (such as a pKaH of 6.5 or greater, e.g. a pKaH of 7 or greater).
In particular embodiments, the base (component (d)) is selected from the group consisting of: carbonate salts; halide salts; metal hydroxides; and metal hydrides, and mixtures thereof. In more particular embodiments, the base is selected from the group consisting oft alkali metal carbonate salts; alkyl ammonium halides; alkali metal hydroxides; and alkali metal hydrides, and mixtures thereof.
For the avoidance of doubt, the skilled person will understand references to alkali metals will refer to metals in Group I of the Periodic Table. In particular, it will refer to Li, Na, K (e.g. Li). In yet more particular embodiments, the base (component (d)) consists of an alkali metal carbonate salt and/or an alkali metal hydroxide.
In particular embodiments, each cationic component of the base (component (d)) is a lithium cation. Particular bases that may be mentioned include Li carbonate salts and Li hydroxides, and mixtures thereof.
In a particular embodiment, the base (component (d)) is selected from the group consisting of Li2C03, LiOH, and mixtures thereof. In a more particular embodiment, the base (component (d)) is U2CO3 (i.e. lithium carbonate).
As described herein, the skilled person will be able to select an amount of suitable base (component (d)) sufficient to allow for the reaction to be performed under basic conditions. In particular, such amount may be selected based on the amount required to deprotonate substantially all of the acid moieties present in the reaction (i.e. the carboxylic acid moieties present in component (b)).
In a particular embodiment, particularly wherein component (b) is a carboxylic acid, the molar amount of component (b) per mole of component (d) is less than 1/n (i.e. (<1)/n; e.g. where n is 2, less than 0.5). In a more particular embodiment, the molar ratio of component (b) to component (d) is in range (from 0.65 to 0.95) / n : 1. In a yet more particular embodiment, the molar ratio of component (b) to component (d) is about 0.75 / n : 1.
The skilled person will understand that the process of the first aspect of the invention may be performed in a suitable solvent, which may be selected based on routine knowledge available to those skilled in the art. Such suitable solvents may be present as an additional component in the process. Alternatively, the reducing agent present (component (c)) may also act as a suitable solvent (i.e. component (c) may be a substance that also acts as a suitable solvent). Thus, component (c) may be a suitable reductant and solvent (i.e. a compound/substance that is a suitable reductant and solvent).
In a particular embodiment, the reducing agent (component (c)) is a suitable solvent (i.e. also acts as a suitable solvent). As described herein, the skilled person will be able to select a suitable reducing agent (which may also act as a suitable solvent) based on routine knowledge available to those skilled in the art. In a particular embodiment, the reducing agent (component (c)), which may also act as a suitable solvent, is an alcohol (i.e. a suitable alcohol). Thus, component (c) may be referred to as a suitable alcohol. Particular such alcohols that may be mentioned include ethanol, methanol, propanol, butanol, pinacol, and ethylene glycol and oligomers thereof.
In a more particular embodiment, the reducing agent (component (c)), which may also act as a suitable solvent, is ethanol. Thus, component (c) may be referred to as ethanol. As described herein, the skilled person will be able to select a suitable amount of component (c), e.g. a suitable amount to act as both reductant and solvent.
The skilled person will understand that the process of the first aspect of the invention may be performed in a suitable reaction vessel and, in particular, under a suitable atmosphere (and at a suitable pressure), which may be determined by those skilled in the art.
For example, the reaction may be performed under an atmosphere of air (e.g. in an open reaction vessel or a vessel charged with air). Alternatively, the reaction may be performed under other suitable atmospheres, such as atmospheres consisting substantially of 02 or Ar, in a suitable reaction vessel (i.e. a closed reaction vessel).
The skilled person will also understand that the process of the first aspect of the invention may be performed in at a suitable temperature, which may be at or, particularly, greater than room temperature (i.e. about 25 °C). In particular, where the reaction is performed in a suitable solvent (as described herein; which may serve as component (c)), the reaction may be performed at a temperature that is the reflux temperature of that solvent (e.g. the reflux temperature of that solvent under an atmosphere of air in an open reaction vessel equipped with suitable apparatus, such as a reflux condenser). For example, where the suitable solvent (e.g. as component (c)) is an alcohol, such as ethanol, the reaction, may be performed at a temperature that is the reflux point of that solvent (e.g. where the solvent is ethanol, at about 78.3 °C).
Without wishing to be bound by theory, it is believed that the process of the first aspect of the invention also allows for preparation of the complex of formula I using lower amounts of carboxylic acid starting material (relative to the source of Rh (III)) than processes of the prior art. In a particular embodiment, the molar ratio of component (a) to component (b) is in the range from 1 : (20/n) to 1 : (2/n). In a more particular embodiment, the molar ratio of component (a) to component (b) is in the range from 1 : (5/n) to 1 : (2/n). In particular, the process of the first aspect of the invention may allow for the preparation of complexes wherein the ligands are large and sterically congested carboxylate groups (and, therefore, the source of X is a large and sterically congested carboxylic acid or salt thereof, such as a large and sterically congested carboxylic acid). In a particular embodiment, X has a minimum of two carbon atoms, such as wherein X is a C2 to C2o carboxylate. In a more particular embodiment, X is a C4 to C20 carboxylate.
In a particular embodiment, X comprises one or two carboxylate groups (such that n represents 4 or 2, respectively).
In a more particular embodiment, X comprises two carboxylate groups (such that n represents 2).
In a yet more particular embodiment, component (b) is a compound of formula II
Figure imgf000013_0001
and X is the corresponding dicarboxylate 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, 02-12 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; X3 and X4 each independently represent H or Ch alky! optionally substituted with one or more F;
Y3 and Y4 each independently represent H or Ci-3 alkyl optionally substituted with one or more F; each Z independently represents halo, Ci-6 alkyl, C2-8 alkenyl or C2-6 alkynyl, wherein the latter three groups are optionally substituted with one or more F; and k represents (an integer from) 0 to 4.
Compounds employed in or produced by the processes described herein (i.e. those involving the process of the first aspect of the invention) may exhibit tautomerism. Thus, the process of the first aspect 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 first aspect 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 cycloalkyi 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 cycloalkyi 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 C„-io aromatic groups. Such groups may be monocyclic, bicyclic or tricyclic and, when polycyclic, be either wholly or partly aromatic. Particular Ce-10 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 cycloalkyl group that is one ring member larger than another will refer to larger rings containing one more such methylene group within the ring structure. In particular embodiments:
X1 and Y1 each independently represent Ci-7 alkyl optionally substituted with one or more F, and X2 and Y2 each independently represent Ci- alkyl, Ci-s 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 cycloalkyl group optionally substituted with one or more F. In further embodiments, k represents 0.
In a more particular embodiments:
X1 and Y1 each independently represent d-3 alkyl optionally substituted by one or more F, and
X2 and Y2 independently represent Ci-e 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 cycloalkyl group optionally substituted with one or more F.
In yet more particular embodiments, either:
X1, X2, Y and Y2 each represent methyl; or
X1 and X2 and Y1 and Y2 are each joined together to form a 5-membered or 6-membered cycloalkyl.
In yet more particular embodiments, X1, X2, Y1 and Y2 each represent methyl.
The skilled person will understand that particular carboxylic acids, and corresponding carboxylate ligands, of interest are those comprising two carboxylic acid groups and having a plane of symmetry positioned between those groups, such that the compounds may be described as being symmetrical.
Thus, in particular embodiments, the compound of formula II is symmetrical. In further embodiments, each of X3, X4, Y3 and Y4 represent H. Thus, in a particular embodiment that may be mentioned: each of X1, X2, Y1 and Y2 represent methyl; each of X3, X4, Y3 and Y4 represent H; and k represents 0.
In a further embodiment that may be mentioned, the compound of formula II is a compound of formula Ha
Figure imgf000017_0001
wherein:
X3, X4, Y3, Y4, Z and k are as defined herein (i.e. as defined for compounds of formula II in the first aspect of the invention, including all embodiments and combinations of embodiments thereof); and m represents 1 or 2. In a particular embodiment (particular in relation to compounds of formula Ha), each of X3, X4, Y3 and Y4 represent H, and k represents 0.
In a more particular embodiment, m represents 1. Thus, in particular embodiments that may be mentioned: component (b) is a compound of the following structure
Figure imgf000018_0001
X represents a corresponding carboxylate of the following structure
Figure imgf000018_0002
or a tautomer thereof; and n (as defined for the complex of formula I) represents 2.
In a particular embodiment, the step of reacting components (a) and (b) in the process of the first aspect of the invention may be 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 will be performed without purification (for example, by chromatography or distillation) of any intermediate compound prior to completion of the final chemical transformation. In a particular embodiment that may be mentioned, the process of the first aspect of the invention further comprises the step of preparing the compound of formula II via a process comprising reacting a corresponding compound of formula III
Figure imgf000019_0001
wherein: each of X1a and X1b represents an X1 group as defined for compounds of formula II, each of Y1a and Y1b represents a Y1 group as defined for compounds of formula II, X2a represents an X2 group as defined for compounds of formula II, and
Y2a represents a Y2 group as defined for compounds of formula II; or either or both of X1a and X2a and Y a and Y2a 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
X1b and Y1b each independently represent Ci-12 alkyl optionally substituted with one or more F, wherein the rings formed by X1a and X2a and Y a and Y2a in the compound of formula III are one ring member larger than the rings formed by X1 and X2 and Y1 and Y2 in the compound of formula II; and
X3, X4, Y3, Y4, Z and k are as defined for compounds of formula II, wherein the reaction of the compound of formula III to form the compound of formula II is performed in the presence of a source of hydrogen peroxide, and optionally in the presence of a suitable solvent. Suitable salts (e.g. of compounds of formula II) that may be mentioned 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 II obtained from the process of the invention will depend on the substituents present in the compound of III reacted, and so will be able to select the substituents for the compound of formula III accordingly.
For example, the skilled person will understand that, if in the compound of formula II the required X1 and X2 are joined together to form, together with the atom to which they are attached, a 5-membered cycloalkyl group, the process will require reacting a compound of formula III wherein X1a and X2aare joined together to form, together with the atom to which they are attached, a 6-membered cycloalkyl 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 III may be selected in order to provide the same group(s) in the compound of formula II. In certain embodiments of the process of the invention:
X1 and Y1 each independently represent C alkyl (e.g. Ci-6 alkyl) optionally substituted with one or more F, and X2 and Y2 each independently represent Gi-7 alkyl (e.g. Gi-6 alkyl), C2-s alkenyl, 02- 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 Y 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 X1a, X1b, Y1a and Y1b each independently represent Ci-7 alkyl (e.g. Ci-6 alkyl) optionally substituted with one or more F, and
X2a and Y2a each independently represent Ci-7 alkyl (e.g. C1-B 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 X1a and X2a and Y a and Y2a 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
X1 and Y1beach independently represent Ci-6 alkyl optionally substituted with one or more F, wherein the rings formed by X1a and X2a and Y1a and Y a 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 particular such embodiments (i.e. the embodiments described above), the X1, X1a, X1b, Y1, Y1a and Y1b 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 a and Y2 and Y2a groups may each independently represent Ci-6 alkyl (including C3-e cycloalkyl, such as Ci-s 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 X2a and Y2 and Y2a groups may each independently represent Ci-5 linear or branched (e.g. linear) alkyl, Cs-e cycloalkyl, C2-4 alkenyl or benzyl, such as linear Ci-5 alkyl, cyclohexyl, -CH2-CHCH2 (i.e. allyl) or benzyl.
As described herein, X1b and Y1 in compounds of formula III may represent a group selected from X1 and Y1 groups, respectively, as defined for compounds of formula II. The skilled person will understand that, in certain embodiments, the X1b and Y1b groups in compounds of formula III are not retained in the compound of formula II. Moreover, the skilled person will understand that in particular such embodiments, X1a and Y1a may correspond to the X1 and Y1 groups, respectively, in compounds of formula !!. Thus, in certain embodiments, X1b and Y b may each independently represent Ci-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 II, and either or both of X1a and X2 and Y1a and Y2 in the compound of formula III, may be linked to form, together with the atom to which they are attached, a cycloalkyi group optionally substituted with one or more F, wherein the rings formed by X1a and X2a and Y1a and Y2a in the compound of formula III are one ring member larger than the rings formed by X1 and X2 and Y1 and Y2 in the compound of formula II. in such embodiments, X b and Y1b may each independently represent Ci-6 alkyl.
In more such particular embodiments, X1b and Y1 may each independently represent Ci-3 alkyl, such as methyl.
In yet more particular such embodiments, X1 and X2 and Y1 and Y2 in a compound of formula II may be each linked to form a 5-membered cycloalkyi group, and X1a and X2a and Y1a and Y2a in a compound of formula III may be each linked to form a 6-membered cycloalkyi 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-6 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 Ci-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:
V1 y1a y1b v1 Via v1b X2 and X2a and Y2 and Y2a each independently represent Ci-7 alkyl (e.g. Ci-e alkyl), allyl or benzyl; and X3, X4, Y3 and Y4 each represent H.
In further embodiments that may be mentioned:
X1, X1a, X1b, X2, X2a Y1, Y a, Y1b, Y2 and Y2a each represent methyl; and
X3, X4, Y3 and Y4 represent H.
In yet further embodiments that may be mentioned: in the compound of formula II, 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 III, X1a and X2a and Y1a and Y2a are each joined together to form a 6-membered or 7-membered cycloalkyl, wherein the ring formed by X1 and X2 and Y and Y2 in the compound of formula II is one ring member larger than the ring formed by X1a and X2a and Y1a and Y2a in the compound of formula III; and X1b and Y1 each represent methyl.
In yet further embodiments: in the compound of formula II, X1 and X2 and Y1 and Y2 are each joined together to form a 5-membered cycloalkyl; in the compound of formula III, X1a and X2a and Y1a and Y2a are each joined together to form a 6-membered cycloalkyl; and X1b and Y1b each represent methyl.
In particular embodiments that may be mentioned: in the compound of formula II, X1 and X2 and Y and Y2 are each joined together to form a
5- membered cycloalkyl; in the compound of formula III, X1a and X2a and Y1a and Y2a are each joined together to form a 6-membered cycloalkyl;
X b and Y1 each represent methyl; X3, X4, Y3 and Y4 represent hydrogen; and k represents 0.
In further embodiments that may be mentioned: in the compound of formula II, X1 and X2 and Y1 and Y2 are each joined together to form a
6- membered cycloalkyl; in the compound of formula III, X1a and X2a and Y1a and Y2a are each joined together to form a 7-membered cycloalkyl;
X and Y1b each represent methyl;
X3, X4, Y3 and Y4 represent hydrogen; and k represents 0.
In further embodiments that may be mentioned: in the compound of formula II, X1, X2, Y and Y2 each represent methyl; in the compound of formula III, X a, X2a, Y1a and Y2a methyl; X3, X4, Y3 and Y4 represent hydrogen; and k represents 0, more particularly wherein X1b and Y1b each represent methyl.
Particular compounds of formula II and III that may be mentioned include those wherein each corresponding pair of X1 and Y\ X1a and Y1a 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,
X1a and Y1a may represent the same group,
X1b and Y1 may represent the same group,
X2 and Y2 may represent the same group,
X2a and Y2a 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, X1a and X2a, and Y1a and Y2a 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 II, 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, C2-12 alkenyl, C2-12 alkynyl, aryl or Ci-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 a!! embodiments of the compounds of the in vention listed hereinabove and equally to compounds of formula III.
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 II and the X1a to X4 and the Y a to Y4 bearing diketone substituents on the aromatic ring in the compound of formula III will be the same. As described herein, depending on the type and position of the Z substituent(s), if any, the compounds of formula II and formula III may be symmetrical (i.e. having a plane of symmetry between the carboxylic acid substituents on the central ring in compounds of formula II and III). 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. For the avoidance of doubt, in particular embodiments of the process of the invention, the compounds of formulae II and III are symmetrical.
The skilled person will understand that, in compounds of formula II, 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 Z1, Z2, Z3 and Z4, respectively.
Thus, in a particular embodiment of the process of the invention, the compound of formula II is a compound of formula lib
Figure imgf000026_0001
or a salt thereof, wherein X1, X2, X3, X4, Y1, Y2, Υ3 and Υ4 are as defined herein (i.e. for compounds of formula II, 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 of formula II 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, Ci-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, Ci-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 certain embodiments of the process of the first aspect of the invention, wherein the process is a process for the preparation of a compound of formula lib, or salt thereof, the g a compound of formula
Figure imgf000028_0001
(lllb) wherein X1a, X1b, X2a, X3, X4, Y1a, Y1b, Y2a, Y3, Y4, Z\ Z2, Z3 and Z4 are as defined herein.
In certain embodiments, Z1 to Z4 each represent H.
In a further embodiment, the compound of formula II is a compound of formula lie
Figure imgf000028_0002
or a salt thereof, wherein X1, X2, X3, X4, Y1, Y2, Y3 and Y4 are as defined hereinabove. In such embodiments, wherein the compound of formula II is a compound of formula lie, or a salt thereof, the skilled person will understand that the process comprises reacting a compound of formula 111
Figure imgf000029_0001
wherein X1a, X1b, X2a, X3, X4, Y1a, Y1b, Y2a, Y3 and Y4 are as defined herein. As described herein, the compound for formula II may be a compound of formula lla. In such embodiments, the compound of formula III may be a compound of formula Ilia
Figure imgf000029_0002
wherein X1b, X3, X4, Y1b, Y3, Y4 and k are as defined herein (i.e. for compounds of formula II, including all embodiments and combinations of embodiments thereof), and m' represents m + 1.
Thus, where the compound of formula II is the compound
Figure imgf000029_0003
the compound of formula III will be a compound of formula
Figure imgf000030_0001
wherein X1b and Y1b are as defined herein (i.e. for compounds of formula III, including all embodiments and combinations of embodiments thereof).
The process for preparing the compound of formula II may be facilitated by the addition of a suitable base, which may have a catalytic effect. Thus, in a particular embodiment, the reaction for preparing the compound of formula II is optionally performed in the presence of a suitable base B1. In a more particular embodiment, the reaction for preparing the compound of formula II is performed in the presence of a suitable base B1.
Suitable bases that may be employed as B1 in the process for preparing the compound of formula II 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 KO¾u, CaO, MgO and Al203 (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 for preparing the compound of formula II may be facilitated by the addition of a suitable acid, which may have a catalytic effect. Thus, in a further embodiment, the reaction for preparing the compound of formula II may optionally be performed in the presence of a suitable acid A1. In a more particular embodiment, the reaction for preparing the compound of formula II is performed in the presence of a suitable acid A1. The suitable acid A1 may be a mineral acid (such as, HCI, H2S04, HN03 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 for preparing the compound of formula II, 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 for preparing the compound of formula II, the source of hydrogen peroxide is aqueous hydrogen peroxide.
The skilled person will understand that the process for preparing the compound of formula II may be performed with a range of equivalents of hydrogen peroxide with respect to (i.e. relative to) the compound of formula III. 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 III, 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 for preparing the compound of formula II 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 III.
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 for preparing the compound of formula II 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 for preparing the compound of formula II 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, Λ ,/V-dimethylformamide and 1',1 ',1'-trifluorotoluene, and mixtures thereof. The skilled person will understand that the process for preparing the compound of formula II 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 II are not linked, the process for preparing the compound of formula II 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 used for the process for preparing the compound of formula II 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, within about 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, si uch as those wherein X1 and X2 and Y1 and Y2 in the compound of formula II 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 for preparing the compound of formula II, 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 II 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 B ). According to a further embodiment, there is provided the process of the first aspect of the invention, which further comprises the step of preparing the compound of formula III as defined hereinabove, which step comprises reacting a compound of formula IVa
Figure imgf000034_0001
wherein X1a, X and X2a are as defined hereinabove; and a compound of formula IVb
Figure imgf000035_0001
wherein Y1a, Y1b and Y2a are as defined hereinabove; with a compound of formula V
Figure imgf000035_0002
wherein:
X3, X4, Y3 and Y4, Z and k 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 (to prepare the compound of formula III) 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 for preparing a compound of formula II is a process for the preparation of a compound of formula lib, the step of preparing a compound of formula III as defined hereinabove, comprises reacting a compound of formula IVa and a compound of formula IVb with a compound of formula Va
Figure imgf000035_0003
wherein X3, X4, Y3, Y4, Z\ Z2, Z3, Z4, LG1 and LG2 are as defined herein. !n embodiments where the process for preparing a compound of formula ii is a process for the preparation of a compound of formula lie, the step of preparing a compound of formula III as defined hereinabove, comprises reacting a compound of formula IVa and a compound of formula IVb with a compound of formula Vb
Figure imgf000036_0001
wherein X3, X4, Y3, Y4, LG1 and LG2 are as defined herein.
In certain embodiments (i.e. certain embodiments of the process for preparing the compound of formula III), 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 rnay be mentioned, LG1 and LG2 may be the same group.
In certain embodiments (i.e. certain embodiments of the process for preparing the compound of formula III), 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, KOSu, 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. KO¾u 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 KO¾u. In more particular embodiments:
LG1 and LG2 are either both CI or both Br; and/or (e.g. and)
Figure imgf000037_0001
In some embodiments, the step of the preparation of a compound of formula III 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 skilled person will understand that preparation of a compound of formula III may be performed at a range of temperatures and in a range of solvents.
Particular temperatures that may be mentioned (i.e. for the process for preparing the compound of formula III) 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 (i.e. for the process for preparing the compound of formula III) 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 i-butanol and 1 ,2-dimethoxy ethane.
Particularly preferred conditions for the step of the preparation of a compound of formula III involve heating to reflux (i.e. around 85 °C) in 1 ,2-dimethoxyethane.
For the avoidance of doubt, 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. The skilled person will understand that the step of preparing a compound of formula iii is performed with at least one equivalent of the compound of formula IVa and at least one equivalent of the compound of formula IVb with respect to the compound of formula V. 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 II (and, therefore, particular compounds of formula III) that may be mentioned include those that are symmetrical. Thus, the skilled person will understand that in particular embodiments the compounds of formula IVa and IVb may be the same.
In such embodiments, the skilled person will understand that the step of preparing a compound of formula III is performed with at least two equivalents of the diketone compound (i.e. the compound of formula IVa and IVb) with respect to the compound of formula V. 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 for preparing the compound of formula III (in particular those wherein X1 and X2 and Y and Y2 in the compound of formula II, and thus also X1a and X2a and Y1a and Y2a in the compound of formula III, are not linked), there is provided the process of the invention comprising the step of preparing a compound of formula III, which further comprises the step(s) of preparing the compound of formula IVa and/or (e.g. and) the compound of formula IVb, which step(s) comprise(s) reacting a compound of formula VI
Figure imgf000038_0001
wherein:
R1a represents X1a or Y1a as hereinabove defined, as required; and R1 represents X1b or Y1 as hereinabove defined, as required, with a compound of formula VII R2-LG3 (vii) wherein:
R2 represents X2a or Y2a 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 K2C03, Na2C03, Cs2C03 K3P04, NaOH and KOH (e.g. K2C03). Thus, in 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 K2C03, Na2C03, Cs2C03, K3P0 , 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 IVa and/or (e.g. and) IVb may be performed at a range of temperatures and in a range of solvents. Particular temperatures that may be mentioned (i.e. for the preparation of a compound of formula IVa and/or IVb) 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 (i.e. for the preparation of a compound of formula IVa and/or IVb) include alcohols (e.g. methanol, ethanol, /-propanol or f-butanol), ethers (e.g. methyl i-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 Iva or IVb involve heating under reflux conditions in acetone (e.g. at around 56 °C).
The skilled person will appreciate that the optimum parameters for the preparation of a compound of formula IVa and/or IVb, 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 II, and thus also X1a and X2a and Y1a and Y2a in the compound of formula III, are not linked, the compound of formula IVa and/or (e.g. and) IVb 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 IVa and/or (e.g. and) IVb and preparing a compound of formula III are performed as a one pot process. In embodiments where the steps of preparing a compound of formula IVa and/or (e.g. and) IVb and a compound of formula II is a one-pot process, a particular such process may comprise; i) heating a compound of VI and a compound of formula VII in the presence of a suitable base (e.g. K2C03) 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 V to the reaction vessel (optionally at room temperature) then heating the reaction at reflux.
Particular compounds of formula II and (corresponding) compounds of formula III that may be mentioned include those of the examples as provided hereinbelow. Similarly particular (corresponding) compounds of formulas Iva, IVb, V, VI and VII that may be mentioned include those of the examples as provided hereinbelow. For the avoidance of doubt, particular processes of the first aspect of the invention that may be mentioned include those of the examples as provided hereinbelow.
The skilled person will understand that complexes of formula I prepared using the process of the first aspect of the invention, particular wherein the process comprises the preparation of a compound of II using a process as described herein, may have characteristic features that would distinguish such complexes over complexes prepared using processes as described in the prior art. In a second aspect of the invention, there is provided a complex of formula I, as defined herein, obtainable or obtained using the process of the first aspect of the invention (including all embodiments and combinations of embodiments thereof).
In particular, the skilled person will understand that compounds of formula II prepared using the process for the preparation of compounds of formula II as described herein may comprise characteristic impurities resulting from the process used for their preparation, which impurities may also be present in complexes of formula I.
For example, such characteristic impurities may be one or more of: a compound of one or more of formulas (a) to (c)
Figure imgf000042_0001
(a) (b) (c) wherein X1, X2, X3, X4, Y\ 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 III, as defined hereinabove;
a compound of formula IVa or IVb, as defined hereinabove;
a compound of formula V, as defined hereinabove;
a compound of formula VI, as defined hereinabove; and/or (e.g. or)
a compound of formula VII, as defined hereinabove.
In particular, the complex of formula I may comprise, 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.
Furthermore, the characteristic impurity may be a by-product (i.e. a side product) resulting from the process for preparing the compound of formula III and/or the product of reacting a by-product resulting from the process for preparing the compound of formula III in the process for preparing a compound of formula II.
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 III 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 compound of formula III may be the compound below.
Figure imgf000042_0002
In such instances, the product of reacting a by-product resulting from the process for preparing the compound of formula III in the process for preparing a compound of formula II may be one or more of the compounds shown in Table 1 below.
Figure imgf000044_0001
Figure imgf000045_0001
Table 1 : Characteristic impurities
In such instances, the characteristic impurity, or mixture of such impurities, may be present in an amount of less than 5% (e.g. less than 1 %) by weight of a sample of the complex of formula I.
As described herein, the process of the first aspect 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 direct synthesis of commercially important complexes (including catalysts used in synthetic processes) from readily available starting materials (e.g. Rh(lll) salts), and using lower amounts of certain starting materials (e.g. carboxylic acid ligands) than processes of the prior art, thus allowing for a more cost-efficient manufacturing process.
Figures
Figure 1 illustrates the comparative catalytic activities of Rh2(cpesp)2 and Rh2(esp)2 in a C-H amination process as described in Example 19 herein below.
In particular, Figure 1 shows that the use of Rh2(cpesp)2 resulted in improved yields (as determined by 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 4. E am les
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 1H-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 KMn04 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 (1H) and at 100 MHz (13C). Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCI3 (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 (Jin 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 Badeiin 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 1a - Synthesis of rhodium (II) trimethylacetate dimer (Rh2(Piv)4) (50 mq scale) U2CO3 (53 mg, 0.718 mmols, 3.7 equiv.) and pivalic acid (55.5 mg, 0.543 mmols, 2.8 equiv.) were suspended in ethanol (99.5%, 10 mL), in a 20 mL pressure tube. Rhodium chloride hydrate (81.2 % wt, 50 mg, 0.194 mmols) was added and the suspension was stirred at room temperature for 30 min and then heated up to 90°C (aluminium block temperature) for 4 hours. The green suspension was concentrated under vacuum and the residue was dissolved in CH2CI2 (50 mL) and washed with a saturated solution of NaHC03 (20 mL), brine (20 mL), and dried over Na2S04. Filtration and evaporation of the solvent at reduced pressure yielded a greenish powder that was purified by column cromatography using AcOEt: petroluem ether (1 :5) as an eluent. (46 mg, 0.075 mmols, 78 % yield). The spectroscopic data matched those reported in the literature (Alvarifio, C. er a/., Chemistry - A European Journal, 21(24), 8851-8858 (2015)), showing H NMR (400 MHz, Chloroform-d) 1.00 (s, 36H).
Example 1 b - Synthesis of rhodium (II) trimethylacetate dimer (Rh2(Piv)4) (250 mg scale) L12CO3 (265 mg, 3.59 mmols, 3.7 equiv.) and pivalic acid (277 mg, 2.72 mmols, 2.8 equiv.) were suspended in ethanol (99.5%, 50 mL), in a 100 mL round bottom flask equipped with a reflux condenser. Rhodium chloride hydrate (81.2 % wt, 250 mg, 0.970 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then, heated up gradually to 80°C (silicone bath temperature) using the following temperature ramp: r.t to 50°C (2°C/min), 10 min at 50 degrees, 50°C to 60°C (2°C/min), 1 hour at 60°C, 60*C to 70°C (2"C/min), 30 min at 70°C, 70°C to 80°C (2'C/min), 2.5 hours at 80°C. The green suspension was concentrated under vacuum and the residue was dissolved in CH2CI2 (200 mL) and washed with a saturated solution of NaHC03 (100 mL), brine (100 mL), and dried over Na2S04. Filtration and evaporation of the solvent at reduced pressure yielded a greenish powder that was purified by column chromatography using AcOEt: petroluem ether (1 :5) as an eluent. (162 mg, 0.265mmols, 55 % yield). The spectroscopic data matched those reported in the literature (ibid.). Example 2a - Synthesis of Rhodium (II) triphenylacetate dimer (Rh2(TPA) ) (50 mq scale)
U2CO3 (28.7 mg, 0.388 mmols, 2 equiv.) and triphenylacetic acid (112 mg, 0.388 mmols, 2 equiv.) were suspended in ethanol (99.5%, 10 mL) in a 20 mL pressure tube. Rhodium chloride hydrate (81.2 % wt, 50 mg, 0.194 mmols) was added and the suspension was stirred at room temperature for 30 min and then heated up to 90°C (aluminium block temperature) for 4 hours. The greenish suspension was concentrated under vacuum and the residue was dissolved in CH2CI2 (50 mL). The organic phase was washed with a saturated solution of NaHC03 (20 mL) with brine (20 mL), and dried over Na2S04. Filtration and evaporation of the solvent at reduced pressure yielded a greenish powder that was purified by column chromatography using CH2CI2 (77 mg, 0.057 mmols, 59 % yield). The spectroscopic data matched those reported in the literature (Hashimoto, S. et al., Tetrahedron Lett., 33(19), 2709-2712 (1992)), showing 1H NMR (400 MHz, Chloroform-d) 6 7.14 - 6.96 (m, 1 H), 6.98 - 6.76 (m, 2H), 6.75 - 6.47 (m, 2H).
Example 2b - Synthesis of Rhodium (II) triphenylacetate dimer (Rh2(TPA)4) (125 mq scale)
Li2C03 (108 mg, 1.455 mmols, 3 equiv.) and triphenylacetic acid (280 mg, 0.97 mmols, 2 equiv.) were suspended in ethanol (99.5%, 25mL) in a 50 mL round bottom flask equipped with a reflux condenser. Rhodium chloride hydrate (81.2 % wt, 125 mg, 0.485 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then heated up gradually to 80°C (silicone bath temperature) using the following temperature ramp: r.t to 50°C (2°C/min), 10 min at 50 degrees, 50°C to 60°C (2°C/min), 1 hour at 60°C, 60 to 70°C (2'C/min), 30 min at 70 , 70 to 80°C (2°C/min), 2 hours at 80°C. The reaction was cooled down and the solvent was removed under vaccum, and the residue was coevaporated twice with chlorobenzene (10 mL) to remove possible traces of ethanol. Chlorobenzene (25 mL) and a third equivalent of triphenylacetic acid (140 mg, 0.485 mmols, 1 equiv.) was added and the mixture was heated up gradually to 140°C (2°C/min) and kept at 140' C for 14 hours. The greenish suspension was concentrated under vacuum and the residue was dissolved in CH2CI2 (150 mL). The organic phase was washed with a saturated solution of NaHC03 (50 mL) with brine (50 mL), and dried over Na2S04. Filtration and evaporation of the solvent at reduced pressure yielded a greenish powder that was purified by column chromatography using CH2CI2: petroleum ether (1 :1 to 1 :4) (204 mg, 0.151 mmols, 62 % yield). The spectroscopic data matched those reported in the literature (ibid.). Example 3a - Synthesis of Rhodium (II) f(a.a,a',a'-tetramethyl-1 ,3-benzenedipropionic acid)ldimer (Rh2(esp)?) (50 mg scale)
U2CO3 (53 mg, 0.718 mmols, 3.7 equiv.) and a,a,a',a'-Tetramethyl-1 ,3-benzenedipropionic acid (76 mg, 0.272 mmols, 1.4 equiv.) were suspended in ethanol (99.5%, 10 mL) in a 20 mL pressure tube. Rhodium chloride hydrate (81.2 % wt, 50 mg, 0.194 mmols) was added and the suspension was stirred at room temperature for 30 min and then heated up to 90°C (aluminium block temperature) for 4 hours. The green suspension was concentrated under vacuum and the residue was dissolved in EtOAc (50 mL). The organic phase was washed with brine (20 mL), and dried over Na2SC>4. Filtration and evaporation of the solvent at reduced pressure yielded a greenish oil that was purified by column chromatography using AcOEt: petroluem ether (1 :7) as an eluent. (54 mg, 0.071 mmols, 75 % yield). The spectroscopic data matched those reported in the literature (Espino, C. G. et a/., J. Am. Chem. Soc, 126(47), 15378 - 15379 (2004)), showing 1H NMR (400 MHz, Methanol-tf4:Chloroform-d (1 :1)) δ 6.67 (t, J = 7.5 Hz, 2H), 6.60 (t, J = 1.8 Hz, 2H), 6.46 (dd, J = 7.5, 1.8 Hz, 4H), 2.26 (s, 4H), 0.63 (s, 12H).
Example 3b - Synthesis of Rhodium (II) r(a,a,a',a'-tetramethyl-1 ,3-benzenedipropionic acidVldimer (Rh2(esp)2) (250 mg scale)
L12CO3 (222 mg, 3.01 mmols, 3.1 equiv.) and α,α,α',α'-Tetramethyl-l ,3-benzenedipropionic acid (270 mg, 0.970 mmols, 1.0 equiv.) were suspended in ethanol (99.5%, 50 mL) in a 100 mL round bottom flask equipped with a reflux condenser. Rhodium chloride hydrate (81.2 % wt, 250 mg, 0.970 mmols) was added and the suspension was vigorously stirred at room temperature for 30 min and then, heated up to 80°C (silicone bath temperature) using the following temperature ramp: r.t to 50°C (2°C/min), 10 min at 50 degrees, 50°C to 60°C (2°C/min), 1 hour at 60°C, 60"C to 70°C (2°C/min), 30 min at 70°C, 70°C to 80°C (2°C/min), 2.5 hours at 80°C. The colour of the suspension was changing from deep red to brown and finally green. The green suspension was concentrated under vacuum and the residue was dissolved in EtOAc (200 mL). The organic phase was washed with brine (100 mL), and dried over Na2S04. Filtration and evaporation of the solvent at reduced pressure yielded a greenish oil that was purified by column chromatography using AcOEt: petroluem ether (1 :7) as an eluent. (190 mg, 0.250 mmols, 52 % yield). The spectroscopic data matched those reported in the literature (ibid.).
Example 4 - Screening of reaction conditions RhCI3 hydrate (81.2% wt, 5 mg, 0.0194 mmols), the appropriate carboxylic acid ligand (in the amounts indicated), and the base (in the amounts indicated), were suspended in EtOH (99.5%, 1 mL) in a closed vial and stirred at room temperature for 30 min under air (unless indicated otherwise). Then, the vial was warmed to 90DC (aluminium block temperature) for 4 hours (unless indicated otherwise). The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate (when α,α,α',α'-tetramethyl-l ,3- benzenedipropionic acid was used as carboxylic acid ligand; 3 mL) or CH2CI2 (when trimethylacetic acid or triphenylacetic acid was used as carboxylic acid ligand; 3 mL) and washed with brine (3 mL). When trimethylacetic or triphenylacetic acid were used as ligands, the organic phase was washed additionally with a saturated solution of NaHC03 (3 mL). The organic phase was dried over Na2S04 and the solvent was removed at reduced pressure. The yield of the reaction was quantified by 1H-N R analysis of the reaction crude using 1 ,1 ,2,2-tetrachloroethane as the internal standard.
Preparation of rhodium (II) pivalate
ttui-i, reTiux
4h
Using the general procedure set out above, reaction conditions for the preparation of Rh(ll) pivalate were screened. The conditions used and results obtained are set out in Table 2 below.
Figure imgf000050_0001
Table 2 Reaction conditions: RhCI3.xH20 (5 mg), base, EtOH (1 mL), reflux, 4h. aExpressed per Rh atom (2 equivalents per Rh needed). bCrude yields as determined by H-NMR using 1 ,1 ,2,2-tetracholoroethane as internal standard, isolated yield of the pure complex after chromatography on a 50 mg-scale reaction. d46 mg of product isolated.
Preparation of Rh(ll)2esp2
Using the general procedure set out above, reaction conditions for the preparation of Rh(ll)2esp2 were screened. The conditions used and results obtained are set out in Table 3 below.
Figure imgf000051_0001
Table 3
Reaction conditions: RhCl3.xH20 (5 mg), base, EtOH (1 mL), reflux, 4h. aExpressed per Rh atom (1 equivalent per Rh needed). Crude yields as determined by 1H-NMR using 1 ,1 ,2,2-tetracholoroethane as internal standard. clsolated yield of the pure complex after chromatography on a 50 mg-scale reaction. d54 mg of product isolated. e44 mg of product isolated.
Example 5 - 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) (Compound 1)
Figure imgf000052_0001
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), Me! (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 1H-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 K2C03 (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 EtiO (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-phenyIene)bis(2,2-dimethylpropanoic acid) (espH2; Compound 2)
Figure imgf000053_0001
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) (espH2; 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, CDCfe) δ = 184.3, 137.3, 131.8, 128.7, 127.6, 45.9, 43.5, 24.5.
Example 6 - 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) (CpespH2; Compound 3)
Figure imgf000053_0002
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 K2C03 (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). H 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, CDCb) 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 (cpespH2; Compound 4)
Figure imgf000054_0001
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 ferf-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 ,1 '-(1 ,3- phenylenebis(methylene))dicyclopentanecarboxylic acid (cpespH2, 4) as white solid (90 mg, 0.28 mmol, 71 %). H 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). 3C 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 [C2oH2604 - H]" 329.1758; found 329.1752.
Example 7 - Synthesis of 3,3'-(1.3-phenylene)bis(2-methylbutanoic acid) (Compound 6)
Synthesis of 3,3'-( 1, 3-phenylenebis(methylene))bis(3-ethylpentane-2, 4-dione) (Compound 5)
Figure imgf000055_0001
KjCC 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 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 diethylethenethylacetate (1 :1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 rn!) and ethyiacetate (2 x 20 mi). The yellow fiitrate 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). H 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):
Figure imgf000056_0001
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 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: ethyiacetate (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 [CiSH2604 - H]" 305.1758; found 305.1760.
Example 8 - Synthesis of 3.3'-(1 ,3-phenylene)bis(2-methylbutanoic acid) (Compound 8)
Synthesis of 3,3'-( 1,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione) (Comp
Figure imgf000057_0001
K2C03, Kl, 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 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 diethenethylacetate (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, 1H), 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), 2.1 1 (s, 12H). 3C NMR (101 MHz, CDCI3) δ 206.1 , 136.4, 132.0, 131.3, 128.5, 128.5, 119.5, 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)
Figure imgf000058_0001
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 N R (400 MHz, CDCU) 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), 1.11 (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 [C2OH2B04- H]" 329.1758; found 329.1755.
Example 9 - 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)
Figure imgf000059_0001
K2COj, Kl, 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 (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 ethenethyl 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, CDCb) 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 MR (126 MHz, CDCb) 5 = 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)
Figure imgf000060_0001
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 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-meth.ylbutanoic 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. H 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, CDCb) 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 [C28H2a04- H]" 429.2071 ; found 429.2075. Example 10 - 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)
Figure imgf000061_0001
A round bottom flask equipped with a magnetic stirrer and a reflux condenser on top was loaded with dry potassium feAf-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. R†f>n — ? · S—jvnthpt.sis nf
Figure imgf000062_0001
(Compound 12)
Figure imgf000062_0002
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 stirfor 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 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 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) δ 7.11 (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 [C28H3804 -H]" 413.2697; found 413.2695. Example 11 - 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)
Figure imgf000063_0001
K2C03, D E 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 ethenethyl 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, CDC!j) 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 [C26H3S04+ H]+ 415.2843; found 415.2839. Step 2. Synthesis of 2,2'-(1,3-phenylenebis(methylene))bis(2-methylhexanoic acid) (Compound 14)
Figure imgf000064_0001
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 HC1 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, CDCfe) 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 MR (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 12 - 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)
Figure imgf000065_0001
K2C03, 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 ethenethyl 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. NMR (500 MHz, CDCi3) 5 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)
Figure imgf000066_0001
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 stirfor 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, CDCfe) 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 13 - 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)
Figure imgf000067_0001
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 (0.398 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 (ESl-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 (ESl-TOF) calc'd for [Ci6H2iBr04 - H]" 355.0550; found 355.0551. Example 14 - 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) ( Compou
Figure imgf000069_0001
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 ethenethyl 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 [CZ0H25BrO4 + H]+ 409.1009; found 409.1009. Step 2. Synthesis of 3,3'-(5-bromo-1l3-phenylene)bis(2;2-dimethylpropanoic acid) (Compound 20)
Figure imgf000070_0001
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 [Ci6H2iBr04 - H]" 355.0550; found 355.0548. Example 15 - Synthesis of 1 ,1'-(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)
Figure imgf000071_0001
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 ethenethyl 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).
3C 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 [CzeH^ + H]+ 411.2530; found 411.2533.
Step 2. Synthesis of 1, 1'-(1,3-phenylenebis(methylene))bis(cyclohexane-1-carboxylic acid) (Compound 22)
Figure imgf000071_0002
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 fo 6 hours at 40°C. Then, t e mixture was cooled down tu 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. H 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-d6) 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 [C22H3Q04 - Hf 357.2071 ; found 357.2068.
Example 16 - 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- methylpentane-2,4-dione) (Compound 23)
Figure imgf000072_0001
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 (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 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 Hz, CDC ) δ 6.80 (s, 1 H), 3.40 (s, 4H), 2.1 1 (s, 12H), 2.09 (s, 6H), 1.92 (s, 3H), 1.04 (s, 6H). 13C NMR (101 MHz, CDCb) δ 207.5, 137.9, 136.5, 133.6, 31.1 , 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-tnmethyi-1,3-phenylene)bis(2,2-dimethylpropanoic acid) (Compound 24)
Figure imgf000073_0001
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 -,-. ~ ~. ... . -f -~ j. ~ _u ι— *_:— .j— caw luui ui iui j ui ι centum m i ic ιαο |ja99c ii μι ijcioi . ι ι ic uuian icu ι 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). 3C 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 [Ci9H2604 - H]" 319.1915; found 319.1911.
Example 17 - Scale up of the process (> 100 g) for the synthesis of espH2 (Compound 2)
Step 1. Synthesis of 3,3'-(1,3-phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (Compound 1)
Figure imgf000074_0001
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 K2C03 (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 terf-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 ferf-butyl ether (2 x 1.5 L). The precipitate formed in the filtrate was filtered off and washed with methyl terf-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-dimethyIpropanoic acid) (espH2 Compound 2)
Figure imgf000075_0001
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 EiOAc (900 mL) snd formed layers were separated. The oryanic phas containiny 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: 1st crop 68.41 g (57%) of white solid (dried in vacuo at 40°C for 7 h); 2nd crop 27.09 g (23%) of white solid (dried in vacuo at 40°C for 7 h). HPLC purity of 1st crop is 98 area-% (220 nm); 2nd crop 95 area-% (220 nm). Yields calculated using HPLC purity correction for the starting material. Example 18 - Synthesis of a 1 ,1'-(1 ,3-phenylenebis(methylene)) dicyclopentanecarboxylate rhodium complex (Rh2(cpesp)2: compound 25)
Figure imgf000076_0001
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 until! dryness and the residue was directly loaded on a silica chromatographic column (pentane 10:1 EtOAc) affording Rh2(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 + Nap 885.1357; found 885.1350.
Example 19 - Comparative study of the catalytic activity of Rh2(cpesp)2 (Compound 25) vs Rh2(esp)2 in a C-H amination (nitrenoid insertion) process
Figure imgf000077_0001
The catalytic activity of Rh2(cpesp)2, at a range of catalytic loadings, was compared against the standard commercially available Rh2(esp)2 catalyst in the synthesis of cyclic sulfamate 26 via C-H amination. Yields were determined by 1H 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 mol, 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 1H-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 mol, 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 C-e!ite (20 x 7 mm). The filter cake was rinsed with C.HaC-b (2 x 5 mL) and the combined filtrates were evaporated under reduced pressure. The crude was analyzed by 1H-NMR (CDCI3) using 1 ,1 ,2,2-tetrachloroethane as internal standard. Genera! 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 pmol, 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 H-NMR (CDCI3) 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. 10 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 pmol, 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 1H-NMR (CDCI3) using 1 ,1 ,2,2-tetrachloroethane as internal standard.
The use Rh2(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 4 below and illustrated graphically in Figure 1,
Figure imgf000078_0001
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 4. - Comparative catalytic activity of Rh2(cpesp)2 and Rh2(esp)2 in the synthesis of cyclic sulfamate 26. *% Yield and unreacted starting material determined by 1H NMR using 1 ,1 ,2,2- tetrachloroethane as internal standard.

Claims

1. A process for the preparation of a complex of formula I
Rh(ll)2 Xn (I) wherein:
X represents a ligand comprising one or more carboxylate group; and n represents 1 , 2 or 4, such that the total number of carboxylate groups present in the complex is 4; comprising the step of reacting:
(a) a source of Rh(lll); and
(b) a source of X, wherein the reaction is performed in the presence of:
(c) a suitable reducing agent, and wherein the reaction is performed under basic conditions.
2. The process of Claim 1 , wherein the source of Rh(lll) is a Rh salt, such as a halide salt.
3. The process of any one of Claims 1 to 2, wherein the source of Rh(lll) (component (a)) is RhCI3.
4. The process of any one of Claims 1 to 3, wherein the source of X (component (b)) is a carboxylic acid and/or salt thereof. 5. The process of any one of Claims 1 to 4, wherein the reaction is performed in the performed in the presence of: (d) a suitable base.
6. The process of any one of Claims 1 to 5, wherein the base (component (d)) is selected from the group consisting of: carbonate salts; halide salts; metal hydroxides; and metal hydrides, and mixtures thereof.
7. The process of any one of Claims 1 to 6, wherein the base (component (d)) is selected from the group consisting of: alkali metal carbonate salts; alkyl ammonium halides; alkali metal hydroxides; and alkali metal hydrides, and mixtures thereof.
8. The process of any one of Claims 1 to 7, wherein the base (component (d)) consists of an alkali metal carbonate salt and/or an alkali metal hydroxide. 9. The process of any one of Claims 1 to 8, wherein each cationic component of the base (component (d)) is a lithium cation.
10. The process of any one of Claims 1 to 9, wherein the base (component (d)) is selected from the group consisting of Li2C03, LiOH, and mixtures thereof.
1 1. The process of any one of Claims 1 to 10, wherein the base (component (d)) is
12. The process of any one of Claims 5 to 11 , wherein the molar amount of component (b) per mole of component (d) is less than 1/n.
13. The process of Claim 12, wherein the molar ratio of component (b) to component (d) is in range (from 0.65 to 0.95) / n : 1. 14. The process of any one of Claims 1 to 13, wherein the reducing agent (component (c)) is a suitable solvent.
15. The process of any one of Claims 1 to 14, wherein the reducing agent (component (c)) is an alcohol, such as ethanol, methanol, propanol, butanol, pinacoi, or ethylene glycol or oligomers thereof. (a) to component (b) is in the range from 1 : 20/n to 1 : 2/n.
17. The process of any one of Claims 1 to 16, wherein the molar ratio of component (a) to component (b) is in the range from 1 : 5/n to 1 : 2/n.
18. The process of any one of Claims 1 to 17, wherein X has a minimum of four carbon atoms, such as a C2 to C20 carboxylate. 19. The process of any one of Claims 1 to 18, wherein X comprises one or two carboxylate groups, such that n represents 4 or 2.
20. The process of any one of Claims 1 to 19, wherein component (b) is a compound of formula II
Figure imgf000082_0001
and X is the corresponding dicarboxylate thereof, wherein:
X1 and Y1 each independently represent C1-12 alkyl optionally substituted with one or more F; X2 and Y2 each independently represent G1-12 alkyl, C-2-TZ 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 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 k represents 0 to 4.
21. The process of Claim 20, 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 cycloalkyl group optionally substituted with one or more F.
22. The process of any one of Claims 20 and 21 , 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 cycloalkyl group optionally substituted with one or more F.
23. The process of any one of Claims 20 to 22, wherein either: X1, X2 : Y1 and Y2 each represent methyl; or
X1 and X2 and Y1 and Y2 are each joined together to form a 5-membered or 6-membered cycloalkyl.
24. The process of any one of Claims 20 or Claim 23, wherein:
X1, X2, Y1 and Y2 each represent methyl. 25. The process of any one of Claims 20 to 24, wherein the compound of formula II is symmetrical.
26. The process of any one of Claims 20 to 25, wherein X3, X4, Y3 and Y4 represent H. 27. The process of any one of Claims 20 to 23 and 25 to 26, wherein the compound of formula II is a compound of formula lla
Figure imgf000084_0001
wherein:
X3, X4, Y3, Y4, Z and k are as defined for compounds of formula II in any one of Claims 16 to 19 and 21 to 22; and m represents 1 or 2.
28. The process of Claim 27, wherein X3, X4, Y3 and Y4 each represent H and k represents 0.
29. The process of Claim 27 or Claim 28, wherein m represents 1.
30. The process of any one of Claims 1 to 23 and 25 to 29, wherein: component (b) is
Figure imgf000085_0001
X represents
Figure imgf000085_0002
or a tautomer thereof; and n represents 2.
31. The process of any one of Claims 20 to 30, wherein the process further comprises the step of preparing the compound of formula II via a process comprising reacting a corresponding compound of formula III
Figure imgf000085_0003
wherein: each of X1a and X1b represents an X1 group as defined for compounds of formula II, each of Y1a and Y1b represents a Y1 group as defined for compounds of formula II, X2a represents an X2 group as defined for compounds of formula II, and Y2a represents a Y2 group as defined for compounds of formula II; or either or both of X1a and X2a and Y1a and Y2a 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 X1 and Y1b each independently represent C1-12 alkyl optionally substituted with one or more F, wherein the rings formed by X1a and X2a and Y1a and Y2a in the compound of formula III are one ring member larger than the rings formed by X1 and X2and Y1 and Y2 in the compound of formula II; and
X3, X4, Y3, Y4, Z and k are as defined for compounds of formula II, wherein the reaction of the compound of formula III to form the compound of formula II is performed in the presence of a source of hydrogen peroxide, and optionally in the presence of a suitable solvent.
32. The process of Claim 31 , wherein the reaction of the compound of formula III to form the compound of formula II is performed in the presence of a suitable base B1.
33. The process of Claim 32, wherein the base B1 is a metal hydroxide, a metal alkoxide or a metal oxide.
34. The process of Claim 32 or Claim 33, wherein the base B1 is selected from the group consisting of LiOH, LiOMe, LiQEt, LiO'Bu, NaOH, NaOMe, NaOEt, NaO'Bu, KOH,
KOMe, KOEt and KO'Bu, CaO, MgO and Al203.
35. The process of any one of Claims 32 to 34, wherein the suitable base B is NaOH. 36. The process of any one of Claims 32 to 35, wherein the reaction of the compound of formula III to form the compound of formula II is performed in the presence of a suitable acid A1.
37. The process of Claim 36, wherein the acid A1 is an organic acid.
38. The process of Claim 36 or Claim 37, wherein the acid A1 is acetic acid, trifuoroacetic acid, camphor sulfonic acid or para-toluene sulfonic acid.
39. The process of any one of Claims 31 to 38, wherein the source of hydrogen peroxide is aqueous hydrogen peroxide. 40. The process of Claim 39, wherein the reaction is performed in the presence of from about 3 to about 5 equivalents of hydrogen peroxide.
41. The process of any one of Claims 31 to 40, wherein the process further comprises the step of preparing the compound of formula III via a process comprising reacting a corresponding compound of formula IVa
Figure imgf000087_0001
wherein X1a, X1b and X2a are as defined for compounds of formula III in any one of the preceding claims; and a compound of formula IVb
Figure imgf000087_0002
wherein Y1a, Y1b and Y2a are as defined for compounds of formula III in any one of the preceding claims; with a compound of formula V
Figure imgf000088_0001
wherein: X3, X4, Y3 and Y4, Z and k are as defined for compounds of formula III 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.
42. The process of Claim 41 , wherein the reaction to prepare the compound of formula III is performed with at least one equivalent of the compound of formula IVa and at least one equivalent of the compound of formula IVb with respect to the compound of formula V.
43. The process of Claim 41 or Claim 42, wherein: LG1 and LG2 are each independently selected from the group consisting of CI, Br, I, OMs and OTs; and
B2is selected from the group consisting of K2C03, Na2C03, Cs2C03, K3P04, NaOH, KO¾u. 44. The process of any one of Claims 41 to 43, wherein: LG1 and LG2 are either both CI or both Br; and B2 is K2C03 or KO'Bu.
45. A complex 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 44.
46. A process, complex or compound substantially as described herein, with reference to the examples.
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AIMEE L. CROMBIE ET AL: "Ring Expansion-Annulation Strategy for the Synthesis of Substituted Azulenes and Oligoazulenes. 2. Synthesis of Azulenyl Halides, Sulfonates, and Azulenylmetal Compounds and Their Application in Transition-Metal-Mediated Coupling Reactions", JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 25, 1 December 2004 (2004-12-01), pages 8652 - 8667, XP055515201, ISSN: 0022-3263, DOI: 10.1021/jo048698c *
KAZUMA SANADA ET AL: "Rotational Control of a Dirhodium-Centered Supramolecular Four-Gear System by Ligand Exchange", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 138, no. 9, 29 February 2016 (2016-02-29), US, pages 2945 - 2948, XP055515753, ISSN: 0002-7863, DOI: 10.1021/jacs.5b13515 *
LEGZDINS P ET AL: "The Protonation of Ruthenium- and Rhodium-bridged Carboxylates and their Use as Homogeneous Hydrogenation Catalysts for Unsaturated Substances", JOURNAL OF THE CHEMICAL SOCIETY: SECTION A INORGANIC PHYSICAL THEORETICAL,, no. 19, 1 January 1970 (1970-01-01), pages 3322 - 3326, XP001274711 *

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