The present invention relates to a selective hydrogenation process for the preparation of allyl alcohols.

Unsaturated primary alcohols are important intermediates in the flavour, fragrance and pharmaceutical industries. However, the selective reduction of α,β-unsaturated aldehydes has proven challenging as, thermodynamically, the C=C bond is more easily reduced than the C=0 bond.

The development of reliable hydrogenation conditions with improved carbonyl selectivity in the preparation of allyl alcohols is desirable.

Summary of the Invention

The present invention is more suited to the large-scale manufacture of allyl alcohols from starting material compounds comprising an α,β-unsaturated carbonyl group. In certain embodiments, the process demonstrates excellent selectivity for the C=0 bond. In certain embodiments, the process demonstrates excellent conversion of the starting material to the desired unsaturated primary alcohol product. In certain embodiments, the unsaturated primary alcohols are produced in high yields.

Accordingly, the invention provides a process for the hydrogenation of a compound comprising an α,β-unsaturated carbonyl group to form a compound comprising an allyl alcohol group, wherein the hydrogenation is carried out in the presence of a hydrogenation catalyst, hydrogen gas and an inorganic base in an aqueous solvent, wherein the hydrogenation catalyst is an iron-, ruthenium- or osmium-containing complex.

Definitions

The point of attachment of a moiety or substituent is represented by For example, - OH is attached through the oxygen atom.

"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group. In certain embodiments, the alkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms. The alkyl group may be unsubstituted. Alternatively, the alkyl group may be substituted. Unless otherwise specified, the alkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Typical alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n- hexyl and the like.

The term "cycloalkyi" is used to denote a saturated carbocyclic hydrocarbon group. In certain embodiments, the cycloalkyi group may have from 3-15 carbon atoms, in certain embodiments, from 3-10 carbon atoms, in certain embodiments, from 3-8 carbon atoms. The cycloalkyi group may unsubstituted. Alternatively, the cycloalkyi group may be substituted. Unless other specified, the cycloalkyi group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Typical cycloalkyi groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Alkoxy" refers to an optionally substituted group of the formula alkyl-O- or cycloalkyl-O- , wherein alkyl and cycloalkyi are as defined above.

"Aryl" refers to an aromatic carbocyclic group. The aryl group may have a single ring or multiple condensed rings. In certain embodiments, the aryl group can have from 6-20 carbon atoms, in certain embodiments from 6-15 carbon atoms, in certain embodiments, 6-12 carbon atoms. The aryl group may be unsubstituted. Alternatively, the aryl group may be substituted. Unless otherwise specified, the aryl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl and the like. "Arylalkyl" refers to an optionally substituted group of the formula aryl-alkyl-, where aryl and alkyl are as defined above.

"Aryloxy" refers to an optionally substituted group of the formula aryl-O-, where aryl is as defined above.

"Halo", "hal" or "halide" refers to -F, -CI, -Br and -I.

"Heteroalkyl" refers to a straight-chain or branched saturated hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heteroalkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms. The heteroalkyl group may be unsubstituted. Alternatively, the heteroalkyl group may substituted. Unless otherwise specified, the heteroalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteralkyl groups include but are not limited to ethers, thioethers, primary amines, secondary amines, tertiary amines and the like.

"Heterocycloalkyl" refers to a saturated cyclic hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heterocycloalkyl group may have from 2-20 carbon atoms, in certain embodiments from 2-10 carbon atoms, in certain embodiments, 2-8 carbon atoms. The heterocycloalkyl group may be unsubstituted. Alternatively, the heterocycloalkyl group may be substituted. Unless otherwise specified, the heterocycloalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heterocycloalkyl groups include but are not limited to epoxide, morpholinyl, piperadinyl, piperazinyl, thirranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, thiomorpholinyl and the like.

"Heteroaryl" refers to an aromatic carbocyclic group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). In certain embodiments, the heteroaryl group may have from 3-20 carbon atoms, in certain embodiments, 4-20 carbon atoms, in certain embodiments from 4-15 carbon atoms, in certain embodiments, 4-8 carbon atoms. The heteroaryl group may be unsubstituted. Alternatively, the heteroaryl group may substituted. Unless otherwise specified, the heteroaryl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteroaryl groups include but are not limited to thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, thiophenyl, oxadiazolyl, pyridinyl, pyrimidyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, indolyl, quinolinyl and the like.

"Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with substituents (e.g. 1, 2, 3, 4, 5 or more) which may be the same or different. The group may be substituted with one or more substituents up to the limitations imposed by stability and the rules of valence. The substituents are selected such that they are not adversely affected under the hydrogenation reaction conditions. Examples of substituents include but are not limited to -CF3, -R ^a , -0-R ^a , -S-R ^a , -NR ^a R ^b , - S(0) ₂ -R ^a , -S(0) ₂ NR ^a R ^b and -CONR ^a R ^b , preferably -CF ₃ , -R ^a , -0-R ^a , -NR ^a R ^b - and -CONR ^a R ^b . R ^a and R ^b are independently selected from the groups consisting of H, alkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or R ^a and R ^b together with the atom to which they are attached form a heterocycloalkyl group, and wherein R ^a and R ^b may be unsubstituted or further substituted as defined herein. The substituents for an aryl group include the substituents listed above and, in addition, a -halo group.

Detailed Description

Starting Material Substrate and Product

A compound comprising an α,β-unsaturated carbonyl group is hydrogenated to form a compound comprising an allyl alcohol group.

The compound comprising the α,β-unsaturated carbonyl group may be a compound of formula (A) :

(A) wherein :

Ra, Rb, Rc and Rd are independently selected from the group consisting of H, unsubstituted Ci-C2o-alkyl, substituted Ci-C2o-alkyl, unsubstituted C3-Ci5-cycloalkyl, substituted C3-C15- cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5-C2o-aryl, unsubstituted C3-C20- heteroaryl, substituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C20- heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen; or one or more pairs selected from R _a /Rb, Rb/Rc, Rc/Rd or R _a /Rd are independently linked to form a ring structure with the atoms to which they are attached up to the limitations imposed by stability and the rules of valence.

R _a may be H, in which case the compound (A) is an α,β-unsaturated aldehyde.

Alternatively, R _a may be selected from a group which is not hydrogen i.e. compound (A) is an α,β-unsaturated ketone. In this instance, R _a may be selected from the group consisting of unsubstituted Ci-C2o-alkyl, substituted Ci-C2o-alkyl, unsubstituted C3-C15- cycloalkyl, substituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5-C20- aryl, unsubstituted C3-C2o-heteroaryl, substituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. Ra, Rb, Rc and Rd may be independently selected from the group consisting of -H, unsubstituted Ci-C2o-alkyl, unsubstituted C ₃ -Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, unsubstituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Ra, Rb, Rc and Rd are independently selected from -H and phenyl. In one embodiment, compound (A) is cinnamaldehyde (i.e. R _a and Rb are -H, one of R _c and Rd is phenyl and the other of R _c and Rd is -H). Compound (A) is a cyclic α,β-unsaturated ketone when R _a is linked to form a ring structure with Rb. In this instance, R _c and Rd may be independently selected from the groups defined above or R _c may be linked to form a ring structure with Rd . Compound (A) is also a cyclic α,β-unsaturated ketone when R _a is linked to form a ring structure with Rd . In this instance, Rb and R _c may be independently selected from the groups defined above or Rb may be linked to form a ring structure with R _c .

When Rb is linked to form a ring structure with R _c , R _a and Rd may be independently selected from the groups defined above or R _a may be linked to form a ring structure with Rd . When Rc is linked to form a ring structure with Rd, R _a and Rb may be independently selected from the groups defined above.

The pairs R _a /Rb, Rb/Rc, Rc/Rd or R _a /Rd may be independently interconnected to form substituted or unsubstituted chiral or achiral bridges having a -(CH2) _n skeleton where n=2- 7 (for example, n may be 2, 3, 4 or 5), such as substituted or unsubstituted -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH ₃ )CH(CH ₃ )-, -CH(CH ₃ )CH ₂ CH(CH ₃ )-, l, l'-bipheny- 2,2'-diyl or l, l'-binaphth-2,2'-diyl.

The compound comprising the α,β-unsaturated carbonyl group may be a compound of formula (B) :

(B) wherein : X is an oxygen atom, a sulfur atom or an -N(R _e )- group;

Ra, Rb, Rc, Rd and R _e are independently selected from the group consisting of H, unsubstituted Ci-C2o-alkyl, substituted Ci-C2o-alkyl, unsubstituted C3-Ci5-cycloalkyl, substituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5-C2o-aryl, unsubstituted C3-C2o-heteroaryl, substituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen; or

one or more pairs selected from R _a /R _e , Re/Rb, Rb/Rc, Rc/Rd or R _a /Rd are independently linked to form a ring structure with the atoms to which they are attached up to the limitations imposed by stability and the rules of valence.

When X is an oxygen atom, the compound (B) is a furanyl group:

When X is an sulfur atom, the compound (B) is a thiophenyl group:

When X is an -N(R _e )-, the compound (B) is a pyrrolyl group:

R _a may be H, in which case the compound (B) contains an α,β-unsaturated aldehyde group.

Alternatively, R _a may be selected from a group which is not hydrogen i.e. compound (B) contains an α,β-unsaturated ketone group. In this instance, R _a may be selected from the group consisting of unsubstituted Ci-C2o-alkyl, substituted Ci-C2o-alkyl, unsubstituted C3- Ci5-cycloalkyl, substituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5-C20- aryl, unsubstituted C3-C2o-heteroaryl, substituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen.

Ra, Rb, Rc, Rd and R _e may be independently selected from the group consisting of -H, unsubstituted Ci-C2o-alkyl, unsubstituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, unsubstituted C3-C2o-heteroaryl, wherein the heteroatoms in the C3-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen. In one embodiment, Ra, Rb, Rc, Rd and R _e are -H. In one embodiment, compound (B) is furfuryl aldehyde (i.e. X is an oxygen atom and R _a , Rb, Rc, Rd and R _e are -H).

Compound (B) is a cyclic α,β-unsaturated ketone when X is an -N(R _e )- group and R _a is linked to form a ring structure with R _e . In this instance, Rb, R _c and Rd may be independently selected from the groups defined above or Rb may be linked to form a ring structure with Rc, or Rc may be linked to form a ring structure with Rd .

Compound (B) is also a cyclic α,β-unsaturated ketone when R _a is linked to form a ring structure with Rd . In this instance, R _e (if present), Rb and R _c may be independently selected from the groups defined above or Rb may be linked to form a ring structure with R _c , or R _e (if present) may be linked to form a ring structure with Rb.

When Rb is linked to form a ring structure with R _c , R _e (if present), R _a and Rd may be independently selected from the groups defined above or R _a may be linked to form a ring structure with Rd, or R _e (if present) may be linked to form a ring structure with Rg. When Rc is linked to form a ring structure with Rd, R _e (if present), R _a and Rb may be independently selected from the groups defined above, or R _e (if present) may be linked to form a ring structure with either R _a or Rb.

The pairs R _a /R _e , Re/Rb, Rb/Rc, Rc/Rd or R _a /Rd may be independently interconnected to form substituted or unsubstituted chiral or achiral bridges having a -(CH2) _n skeleton where n=2- 7 (for example, n may be 2, 3, 4 or 5), such as substituted or unsubstituted -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH ₃ )CH(CH ₃ )-, -CH(CH ₃ )CH ₂ CH(CH ₃ )-, l, l'-bipheny- 2,2'-diyl or l, l'-binaphth-2,2'-diyl. The product of the present process is a compound comprising an allyl alcohol group. The allyl alcohol group may be primary allyl alcohol (if the starting material is an α,β- unsaturated aldehyde) or a secondary allyl alcohol (if the starting material is an α,β- unsaturated ketone). The compound of formula (A) may be reduced to a compound of formula (Α') :

(A) (Α') wherein R _a , Rb, R _c , Rd, and the pairs R _a /Rb, Rb/Rc, Rc/Rd and R _a /Rd are as defined above. The compound of formula (B) may be reduced to a compound of formula (Β') :

(B) (Β') wherein R _a , Rb, R _c , Rd, X and the pairs R _a /Rb, Rb/Rc, Rc/Rd and R _a /Rd are as defined above.

The hvdroqenation reaction

Hydrogenation is the addition of molecular hydrogen gas (H ₂ ) to a compound in the presence of a hydrogenation catalyst. The present invention does not relate to transfer hydrogenation, which is the addition of hydrogen to a compound from a source other than hydrogen gas. In the present invention, the hydrogenation reaction is carried out in the presence of a hydrogenation catalyst, hydrogen gas and an inorganic base in an aqueous solvent.

The hydrogenation catalyst is described in more detail below.

The process may be carried out at typical pressures of hydrogen of about 1 bar to about 100 bar, such as about 20 bar to about 85 bar, for example, about 5 bar to about 35 bar can be used.

The inorganic base may be a hydroxide, alkoxide, carbonate, acetate or phosphate, for example, an hydroxide or alkoxide. Suitable hydroxides include alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide) or tetraalkylammonium hydroxides. In one embodiment, the hydroxides may be selected from the group consisting of sodium hydroxide, potassium hydroxide or tetrabutylammonium hydroxide.

Suitable alkoxides include alkali metal alkoxides (e.g. lithium alkoxide, sodium alkoxide or potassium alkoxide) or tetraalkylammonium alkoxides. In one embodiment, the alkoxide is sodium ethoxide or potassium ethoxide. Suitable carbonates include alkali metal carbonates (e.g. lithium carbonate, sodium carbonate or potassium carbonate).

Suitable phosphates include alkali metal phosphates (e.g. lithium phosphates, sodium phosphates or potassium phosphates).

Suitable acetates include alkali metal acetates (e.g. lithium acetates, sodium acetates or potassium acetates).

Without wishing to be bound by theory, it is believed that the inorganic base regenerates the hydrogenation catalyst during use. The base may be used in any suitable quantity, such as from about 0.1 to about 50 mol% to the starting material substrate, for example, about 1 mol% to about 30 mol%, such as about 5 mol% to about 25 mol%.

In one embodiment, the process does not comprise a co-catalyst, such as 4- (dimethylamino)pyridine (DMAP).

The substrate/catalyst (S/C) molar ratio of the starting material substrate to hydrogenation catalyst may in the range of about 100 : 1 to about 200,000 : 1. In some embodiments, the S/C molar ratio may be > about 500 : 1. In some embodiments, the S/C molar ratio may be > about 1000 : 1. In some embodiments, the S/C molar ratio may be > about 2000 : 1. In some embodiments, the S/C molar ratio may be > about 3000: 1. In some embodiments, the S/C molar ratio may be > about 4000 : 1. In some embodiments, the S/C molar ratio may be > about 5000 : 1. In some embodiments, the S/C molar ratio may be > about 10,000 : 1. In some embodiments, the S/C molar ratio may be > about 20,000 : 1. In some embodiments, the S/C molar ratio may be > about 30,000: 1. In some embodiments, the S/C molar ratio may be > about 40,000 : 1. In some embodiments, the S/C molar ratio may be > about 50,000 : 1. In some embodiments, the S/C molar ratio may be < about 200,000 : 1. In some embodiments, the S/C molar ratio may be < about 175,000 : 1. In some embodiments, the S/C molar ratio may be < about 150,000 : 1. In one embodiment, the S/C molar ratio may be in the range of > about 5,000 : 1 to < about 100,000: 1. The beneficial effect of water appears to be most noticeable in the hydrogenation reaction at lower loadings.

An "aqueous solvent" refers to water or a mixture of water and water-miscible solvents. In one embodiment, the aqueous solvent is water. Water may be introduced to the reaction in its own right or as a solution of the base. In another embodiment, the aqueous solvent is water and at least one water-miscible solvent. Any suitable water-miscible solvent may be used which is capable of dissolving the hydrogenation catalyst and which does not adversely affect the chemical conversion of the starting material to the product. The aqueous solvent may be selected from the group consisting of water, alcoholic solvents, water-miscible ether solvents and water-miscible cyclic ether solvents. Examples of alcoholic solvents include but are not limited to methanol, ethanol, propanol (n- or i-) and butanol (n-, i- or t-). Examples of water-miscible ether solvents include but are not limited to polyethyleneglycols (PEGs). Examples of water-miscible cyclic ether solvents include but are not limited to tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), 3-methyl-tetrahydrofuran and 1,4-dioxane. Mixtures of water and water- miscible solvents include but are not limited to water and THF, water and 2-methyl- tetrahydrofuran, water and 3-methyl-tetrahydrofuran, water and ethanol, water and 1,4- dioxane. The molar concentration of the starting material substrate in the aqueous solvent may be between about 0.1-10 M, such as about 3-7 M, for example, about 4-6M.

The process may be monophasic (i.e. homogeneous) or biphasic. When the process is monophasic, the starting material substrate is substantially dissolved in the aqueous solvent, and the aqueous solvent is a mixture of water and water-miscible solvents (as described above) and does not consist solely of water.

The process may be biphasic if the process contains water-immiscible organic solvents. Water-immiscible solvents include but are not limited to aromatic solvents, alkane solvents, and water-immiscible ether solvents. Examples of aromatic solvents include but are not limited to benzene, toluene and xylene. Examples of alkane solvents include but are not limited to low boiling point alkanes, such as pentane isomers, hexane isomers, cyclohexane, heptane isomers and octane isomers. An example of a water-immiscible ether solvent is diethyl ether.

The process may also be biphasic when the starting material substrate is present as a slurry in the reaction mixture. "Slurry" means a heterogeneous mixture of at least a portion of the starting material substrate in the reaction mixture. "Slurry" therefore includes the starting material substrate which is substantially present as a solid, as well as being partially dissolved in the reaction mixture. The advantage associated with carrying out the hydrogenation reaction in the presence of water is that conversion of the starting material substrate to product appears to be greater than the conversion in non-aqueous conditions. Water can be present in any volume which does not adversely affect the chemical conversion of the starting material to the product. For example, water may be present in the process in the range of about 0.1 vol% to 40 vol%. In some embodiments, water may be present in > about 0.1 vol%. In some embodiments, water may be present in > about 0.5 vol%. In some embodiments, water may be present in > about 1 vol%.. In some embodiments, water may be present in < about 40 vol%. In some embodiments, water may be present in < about 35 vol%. In some embodiments, water may be present in < about 30 vol%. In one embodiment, water may be present in a range of about 1 vol % to about 25 vol %.

The process may be carried out at a temperature greater than room temperature (20 °C) and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the aqueous solvents used. In one embodiment, the hydrogenation is carried out at one or more temperatures in the range of > about 20 °C to about < about 100 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures > about 25 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures > about 30 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures > about 35 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 95 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 90 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 85 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 80 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 75 °C. In some embodiments, the hydrogenation is carried out at one or more temperatures < about 70 °C. In one preferred embodiment, the hydrogenation is carried out at one or more temperatures in the range of > about 35 °C to about < 65 °C, such as about 40 °C. The process is carried out for a period of time until it is determined that the reaction is complete. Completion of the reaction may be determined by in-process analysis e.g. by taking a sample of the reaction mixture and analysing it by HPLC to determine conversion. In certain embodiments, the conversion of the starting material to the product is > about 50%. In certain embodiments, the conversion is > about 60%. In certain embodiments, the conversion is > about 70%. In certain embodiments, the conversion is > about 80%. In certain embodiments, the conversion is > about 85%. In certain embodiments, the conversion is > about 90%. In certain embodiments, the conversion is > about 95%. In certain embodiments, the conversion is > about 97%. In certain embodiments, the conversion is substantially 100%. Typically, the reaction is complete within about 24 hours.

The hydrogenation catalyst and the substrate, as well as the inorganic base and aqueous solvent, can be mixed in any suitable order before the hydrogen gas is applied to the reaction mixture. Before the hydrogen is introduced to the reaction vessel, the reaction vessel may be purged with one or more nitrogen/vacuum cycles (e.g. one, two, three, four or five cycles). The hydrogenation process may be carried out for any suitable period of time and this period of time will depend upon the reaction conditions under which the hydrogenation is conducted e.g. substrate concentration, catalyst concentration, pressure, temperature and the like. Once the hydrogenation process has been determined to be complete, the product may be isolated and purified using conventional techniques.

On completion of the reaction, the reaction vessel may be cooled to ambient temperature and optionally purged with one or more inert gas/vacuum cycles (e.g. one, two, three, four or five cycles) to remove excess hydrogen gas. The inert gas may be e.g. nitrogen or argon. The reaction mixture may be treated with a solvent, washed one or more times (e.g. one, two, three or more times) with water or brine, dried (e.g. over magnesium sulfate), and filtered (e.g. through a pad of silica and magnesium sulfate). The product may be obtained by the removal of the organic solvents, such as by increasing the temperature or reducing the pressure using distillation or stripping methods well known in the art. The product may be dried using known methods, for example, at temperatures in the range of about 10-60 °C, such as 20-40 °C, under 0.1-30 mbar for about 1 hour to about 5 days.

Hydrogenation catalyst

The hydrogenation catalyst is an iron-containing complex, ruthenium-containing complex or an osmium-containing complex.

The hydrogenation catalyst may be a complex of formula (I) : [M (Y) ₂ (!_ - (L ² )] (I) wherein :

M is iron, ruthenium or osmium;

Y is an anionic ligand ;

L ¹ is a monodentate phosphorus ligand, or a bidentate phosphorus ligand ;

m' is 1 or 2, wherein,

when m' is 1, L ¹ is a bidentate phosphorus ligand ;

when m' is 2, each L ¹ is a monodentate phosphorus ligand ; and

L ² is a bidentate N,N ligand comprising a nitrogen-containing heteroaryl group and an amino group.

The meta l M is selected from iron, ruthenium or osmium. In one embodiment, M is ruthenium or osmium.

In one embodiment, M is ruthenium. When M is ruthenium, M may be Ru(II). In another embodiment, M is osmium. When M is osmium, M may be Os(II).

Y is an anionic ligand, such as a halide or a carboxylate. When the anionic ligand is a ha lide, the halide may be -CI, -Br or -I, for example, the halide may be -CI .

When the anionic liga nd is a carboxylate ligand, the anionic liga nd may have the formula -OC(0)RA- RA may be selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-2o-heterocycloalkyl, substituted C2-2o-heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl. R _A may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyi groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, na phthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I) or alkoxy groups, e.g . methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g . 1, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl (e.g . methyl), C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g . F3C- ) . Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used . In one embodiment, the carboxylate ligand is an acetate ligand (i.e. -OC(O)Me). In one embodiment, the carboxylate ligand is a pivalate ligand (i.e. -ΟΟ(Ο)'Βιι). In another embodiment, the carboxylate ligand is a benzoate, 2,4,6-trimethylbenzoate or an adamantane-l-carboxylate ligand.

L ¹ may be a monodentate phosphorus ligand and, in this instance, m' is 2. Alternatively, L ¹ is a bidentate phosphorus ligand and, in this instance, m' is 1.

Any suitable phosphorus compound capable of forming a ligand-metal interaction with the M atom may be used. In the ligand, each phosphorus atom is covalently bonded to either 3 carbon atoms (tertiary phosphines) or to n heteroatoms and 3-n carbon atoms, where n = 1, 2 or 3. Preferably, the heteroatom is selected from the group consisting of N and O. The phosphorus ligand may be monodentate, e.g. PP i3, or bidentate. The ligand may be chiral or achiral. The hydrogenation process of the invention produces a compound comprising a primary alcohol group. The process is, accordingly, an achiral reaction and while a chiral phosphine ligand may be conveniently used, the reduction of an aldehyde starting material will not produce a chiral primary alcohol product. A variety of chiral phosphorus ligands has been described and reviews are available, for example see W. Tang and X. Zhang, Chem Rev. 2003, 103, 3029 - 3070 and J.C. Carretero, Angew. Chem. Int. Ed., 2006, 45, 7674-7715.

When L ¹ is a monodentate phosphorus ligand, m' is 2. Each L ¹ may be the same or different. Preferably, L ¹ is a tertiary phosphine ligand PR ⁿ R ¹² R ¹³ . R ¹¹ , R ¹² and R ¹³ may be independently selected from the group consisting of unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C1-20- alkoxy, substituted Ci-20-alkoxy, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-20- heterocycloalkyl, substituted C2-2o-heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl. R ¹¹ , R ¹² and R ¹³ may be independently substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl (e.g . methyl), Ci-Cio alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyi groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g . F3C- ) . Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used . In an alternative embodiment, any two of R ¹¹ , R ¹² and R ¹³ may be linked to form a ring structure with the phosphorus atom, preferably 4- to 7-membered rings. Preferably, R ¹¹ , R ¹² and R ¹³ are the same and are phenyl i.e. PR ⁿ R ¹² R ¹³ is triphenylphosphine. Alternatively, R ¹¹ , R ¹² and R ¹³ may be the same and are tolyl i.e. PR ⁿ R ¹² R ¹³ is tritolylphosphine (e.g . ortho-, meta- or para- tritolylphosphine) .

Alternatively, L ¹ is a bidentate phosphorus ligand and, in this instance, m' is 1. Phosphorus ligands that may be used in the present invention include but are not restricted to the following structural types :

BINAP, R = aryl and alkyl P-PHOS R= aryl, alkyl

= O, S, N

BITIANAP

-BINAP, R = aryl and alkyl R= aryl, alkyl R = aryl, alkyl

X = O, S, N X = O BIBFUP

X = NH or S

JOSIPHOS TANIAPHOS WALPHOS

alkyl, aryl R ¹ = alkyl, aryl R ¹ = alkyl, aryl alkyl, aryl R ² = alkyl, aryl R ² = alkyl, aryl alkyl, aryl R ³ = alkyl BOP

R ¹ =

R ² =

R ³ =

R ⁴ = alkyi, aryl

Me - FERROTANE FERROPHOS

R ¹ = alkyi, aryl R ³ = 3-pentyl

R = alkyi, aryl

n = 3, R = Ph, dppp

n = 4, R = Ph, dppb R = alkyi, aryl

R = Ph, dppf

PARAPHOS

X = functional group

l, alkyl

C _n TUNAPHOS

including:

BPPM BPPM amide DIOP

R ¹ = alkyl, aryl R ¹ = alkyl, aryl R = alkyl, aryl R ² = alkyl, aryl R ² = alkyl, aryl

R ³ = substituted R ³ = alkyl, aryl, OR ⁴ , NR ₂

R ⁴ = alkyl, aryl

BPE -type DUPHOS -type MALPHOS type

R = alkyl, aryl, CH ₂ OR ² R = alkyl, CH ₂ OR ² X = O, NR

R ³ = H or OR ² R ³ = H or OR ²

R ² = alkyl R ² = alkyl

DPPE DAPE DIPAMP CHIRAPHOS DEGPHOS

R ,R ² = phenyl R ¹ ,R ² = alkyl R = phenyl R = R ² alkyl R = aryl

R2 = 4-MeO-phenyl PROPHOS R ¹ = alkyl, aryl, OR ² ,

R ² = alkyl R = H R ² = alkyl, aryl

DPPM DAPM TRICHICKENPHOS

R = R ² = phenyl R1 = R2 = alkyl R ¹ = R ² = tert-Bu TANGPHOS

3 = Me

S EWPHOS

R' = R" = alkyl

Ar = aryl, substituted

aryl

In the above structures -PR ₂ may be -P(alkyl) ₂ in which alkyl is preferably Ci-Cio alkyl, -P(aryl) ₂ where aryl includes phenyl and naphthyl which may be substituted or unsubstituted or -P(0-alkyl) ₂ and -P(0-aryl) ₂ with alkyl and aryl as defined above. -PR ₂ may also be substituted or unsubstituted -P(heteroaryl) ₂ , where heteroaryl includes furanyl (e.g. 2-furanyl or 3-furanyl). -PR ₂ is preferably either -P(aryl) ₂ where aryl includes phenyl, tolyl, xylyl or anisyl or -P(0-aryl) ₂ . If -PR ₂ is -P(0-aryl) ₂ , the most preferred O-aryl groups are those based on chiral or achiral substituted Ι,Ι'-biphenol and l,l'-binaphtol. Alternatively, the R groups on the P-atom may be linked as part of a cyclic structure. Substituting groups may be present on the alkyl or aryl substituents in the phosphorus ligands. Such substituting groups are typically branched or linear Ci-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, tert butyl and cyclohexyl.

The phosphorus ligands are preferably used in their single enantiomer form. These phosphorus ligands are generally available commercially and their preparation is known. For example, the preparation of PARAPHOS ligands is given in WO 04/111065, the preparation of Bophoz ligands in WO02/26750 and US6906212 and the preparation of Josiphos ligands in EP564406B and EP612758B.

The phosphorus ligand L ¹ preferably includes Binap ligands, PPhos ligands, PhanePhos ligands, QPhos ligands, Josiphos ligands and Bophoz ligands. The phosphorus ligand L ¹ includes PP , PCv3 (tricyclohexylphosphine), dppf (1,1'- bis(diphenylphosphino)ferrocene), dppp (l,3-bis(diphenylphosphino)propane), dppb (1,4- bis(diphenylphosphino)butane), Dipfc (l,l'-bis(di-isopropylphosphino)ferrocene), dCyPfc (l,l'-bis(di-cyclohexylphosphino)ferrocene and DB'PF (l, l'-bis(di-tert- butylphosphino)ferrocene), for example, dppf, dppp, dppb and dCyPfc. In one embodiment, the phosphorus ligand L ¹ is unsubstituted. In another embodiment, the ligand L ¹ is substituted.

L ² is a bidentate N,N ligand comprising a nitrogen-containing heteroaryl group and an amino group. The nitrogen-containing heteroaryl group may include a pyridinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, indolyl or quinolinyl groups, preferably pyridinyl. The amino group may comprise primary, secondary or tertiary amino groups, preferably -N H2.

L ² is a bidentate N,N ligand comprising two nitrogen-containing groups. In one embodiment, the bidentate Ν,Ν-ligand comprises a nitrogen-containing heteroaryl group and an amino group.

The nitrogen-containing heteroaryl group may include a pyridinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, indolyl or quinolinyl groups. In one embodiment, the nitrogen- containing heteroaryl group is pyridinyl. In another embodiment, the nitrogen-containing heteroaryl group is a pyrrolyl group. In another embodiment, the nitrogen-containing heteraryl group is a pyrazinyl group. In another embodiment, the nitrogen-containing heteraryl group is a pyrimidinyl group. The amino group may comprise primary, secondary or tertiary amino groups. In one embodiment, the amino group is -NH2.

In another embodiment, the bidentate Ν,Ν-ligand comprises two amino groups. Each amino group may independently comprise primary, secondary or tertiary amino groups. In one embodiment, both amino group are -N H2.

The bidentate Ν,Ν-ligand may be selected from the group consisting of ligands of formulae (1), (2), (3), (4) and (5) :

(1) (2) (3)

The ligands (1), (2), (3), (4) and (5) are bidentate ligands as each ligand coordinates to the M atom through the nitrogen-containing groups. For ligands (1), (2), (4) and (5), each ligand coordinates to the M atom through (a) the amino and (b) the or one of the nitrogen-containing heteroaryl functional groups. For ligand (3), the ligand coordinates to the M atom through the two amino groups.

In one embodiment, the bidentate Ν,Ν-ligand is ligand (1). In another embodiment, the bidentate Ν,Ν-ligand is ligand (2). In another embodiment, the bidentate Ν,Ν-ligand is ligand (3). In another embodiment, the bidentate Ν,Ν-ligand is ligand (4). In another embodiment, the bidentate Ν,Ν-ligand is ligand (5).

The bidentate N,N ligands of formulae (1), (2), (3), (4) and (5) may be added to the reaction mixture as the free base. If salts of the ligands are utilised (e.g. the hydrochloride salt), the salt may be treated with a base (such as triethylamine) in order to liberate the free base of the ligand before the free base is added to the reaction mixture.

Rii and R12 may be independently selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-20- cycloalkyl, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-2o-heterocycloalkyl, substituted C2-20- heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl. In one embodiment, Rn and R12 are independently selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl and substituted C5-2o-aryl, such as -

H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyi groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally functionalised with one or more substituents such as halide (-F, -CI, -Br or -I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally functionalised with one or more (e.g.

I, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl, C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C- )■

In one embodiment, one of Rn and R12 is -H and the other is selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-20- cycloalkyi, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-20- heterocycloalkyl, substituted C2-2o-heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl. In one preferred embodiment, one of Rn and R12 is -H and the other is selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-20- aryl and substituted C5-2o-aryl, such as -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyi groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally functionalised with one or more substituents such as halide (-F, -CI, -Br or -I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally functionalised with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl, C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-) .

In one preferred embodiment, Rn and R12 are both -H.

The integer "a" may be 1 or 2. In one embodiment, the inte er "a" is 1. In this instance,

the side chain of the ligand of formula (2) is odiment, the integer

"a" is 2, in which case, the side chain of th e ligand (2) is . when the integer "a" is 2, each R13 may be the same or different and each R _i4 may be the same or different.

R13 and Ri ₄ may be the same or different. When R13 and Ri ₄ are different, the ligand (1) will contain 1 or 2 chiral centres. The ligand (1) can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (1) may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (1).

R13 and Ri ₄ may be independently selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-20- cycloalkyl, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-2o-heterocycloalkyl, substituted C2-20- heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl. In one embodiment, R13 and Ri ₄ are independently selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl and substituted C5-2o-aryl, such as -

H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (-F, -CI, -Br or -I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g .

I, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl, C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C- ) . More prefera bly, R13 and Ri ₄ are independently selected from -H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl a nd phenyl.

In one embodiment, one of R13 and Ri ₄ is -H and the other is selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-20- cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci-20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-20- heterocycloalkyl, substituted C2-2o-heterocycloalkyl, unsubstituted C ₄ -2o-heteroaryl and substituted C ₄ -2o-heteroaryl . In one preferred embodiment, one of R13 a nd Ri ₄ is -H and the other is selected from the group consisting of -H, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-20- aryl and substituted C5-2o-aryl, such as -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stea ryl, cycloa lkyi groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (-F, -CI, -Br or -I) or alkoxy groups, e.g . methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl, C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloa lkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g . F3C-) . In one embodiment, R13 and Ri ₄ are independently selected from -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl a nd phenyl. In another embodiment, one of R13 and Ri ₄ is -H and the other of R13 and Ri ₄ is selected from the group of consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and phenyl .

The integer b may be 0 or 1. In one embodiment, b is 0, in which case the nitrogen- containing aromatic ring is a pyrrolyl ring . In another embodiment, b is 1. In this instance, the nitrogen-containing aromatic ring is a pyridinyl ring .

R15 may be present or absent. When absent, c is 0 i .e. the pyrrolyl or pyridinyl ring is not substituted . When b is 0, c may be 1, 2 or 3 (i.e. the pyrrolyl ring may have one, two or three R15 groups) . When b is 1, c may be 1, 2, 3 or 4 (i.e. the pyridinyl ring may have one, two, three or four R15 groups) . When c is 2, 3 or where appropriate 4, each R15 may be the same or different to each other. The or each R15 may be independently selected from the group consisting of unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted Ci-20-alkoxy, substituted Ci-20-alkoxy, unsubstituted C5-2o-aryl, substituted C5-2o-aryl, unsubstituted Ci- 20-heteroalkyl, substituted Ci-20-heteroalkyl, unsubstituted C2-2o-heterocycloalkyl, substituted C2-2o-heterocycloalkyl, unsubstituted C4-2o-heteroaryl and substituted C4-20- heteroaryl. Preferably, R15 is independently selected from the group consisting of unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted C5-2o-aryl and substituted C5-2o-aryl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (-F, -CI, -Br or -I) or alkoxy groups, e.g . methoxy, ethoxy or propoxy. The a ryl group may be optionally substituted with one or more (e.g . 1, 2, 3, 4, or 5) substituents such as halide (-F, -CI, -Br or -I), straight- or branched-chain Ci-Cio-alkyl, C1-C10 alkoxy, straight- or branched-chain Ci-Cio-(dialkyl)amino, C3-10 heterocycloalkyl groups (such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g . F3C- ) . Preferably, c is 0 i.e. R15 is absent and the pyridine ring is unsubstituted .

In one preferred embodiment, the bidentate Ν,Ν-ligand (1) is selected from the group consisting of:

In one particular preferred embodiment, the bidentate Ν,Ν-ligand is 2- aminomethylpyridine (AMPY) . For the ligand of formula (2), R21 and R22 may be independently selected from the groups described above for Rn and R12.

The integer bl may be 0 or 1. In one embod iment, bl is 0, in which case the nitrogen- containing aromatic ring is a pyrrolyl ring . In another embodiment, bl is 1. In this instance, the nitrogen-containing aromatic ring is a pyridinyl ring .

R23 may be present or absent. When a bsent, cl is 0 i .e. the pyrrolyl or pyridinyl ring is not substituted . When bl is 0, cl may be 1 or 2 (i .e. the pyrrolyl ring may have one or two R23 groups) . When bl is 1, cl may be 1, 2 or 3 (i.e. the pyridinyl ring may have one, two or three R23 groups). When cl is 2 or where appropriate 3, each R23 may be the same or different to each other. The or each R23 may be selected from the groups described above for R15. In one embodiment, cl is 0 i.e. R23 is absent.

R24 may be present or absent. When absent, c2 is 0. When R24 is present, c2 may be 1, 2 or 3. When c2 is 2 or 3, each R24 may be the same or different to each other. The or each R24 may be selected from the groups described above for R15. In one embodiment, c2 is 0 i.e. R24 is absent.

In one preferred embodiment, the ligand (2) may be:

For ligand (3), R31 and R32 may be independently selected from the groups defined above for R11 and R12. R38 and R37 may independently be selected from the groups defined above

R33, R34, R35 and R36 may each independently be selected from the group consisting of hydrogen, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, substituted C3-2o-cycloalkyl, unsubstituted-C6-2o-aryl, substituted-C6-2o-aryl, unsubstituted-C6-2o-aryloxy and substituted-C6-2o-aryloxy. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, unsubstituted Ci-20-alkoxy, unsubstituted C2-2o-cycloalkoxy, unsubstituted-C ₆ -2o-aryl, unsubstituted-C ₆ -2o-aryloxy, -OH, -CN, -NR ^a R ^b , -COOR ^a , - CONR ^a R ^b and -CF3. R ^a and R ^b are independently selected from the groups consisting of H, Ci-2o a l kyl, C6-20 aryl, arylalkyl, heteroalkyl, C3-20 heteroaryl, or R ^a and R ^b together with the atom to which they are attached form a heterocycloalkyl group.

In one embodiment, R33, R34, R35 and R36 are each independently selected from the group consisting of hydrogen, unsubstituted Ci-20-alkyl, substituted Ci-20-alkyl, unsubstituted-C6- 20-aryl, substituted-C6-2o-aryl, unsubstituted-C6-2o-aryloxy and substituted-C6-2o-aryloxy. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted Ci-20-alkoxy, unsubstituted-C6-2o-aryl, unsubstituted-C6-2o- aryloxy and -OH. In another embodiment, the groups R33, R34, R35 and R36 may each independently be selected from the group consisting of hydrogen, unsubstituted-C6-2o-aryl and substituted-C6-2o-aryl. In another embodiment, R33, R34, R35 and R36 are each independently selected from the group consisting of hydrogen or phenyl. In yet another embodiment, one of R33 and R34 is phenyl and the other of R35 and R36 is hydrogen. In another embodiment, one of R35 and R36 is phenyl and the other of R35 and R36 is hydrogen. In one embodiment, R33, R34, R35 and R36 are each hydrogen.

R33 and R34 together with the carbon atom to which they are bound and/or R35 and R36 together with the carbon atom to which they are bound may form an unsubstituted C3-20- cycloalkyl or substituted C3-2o-cycloalkyl. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, unsubstituted Ci-20-alkoxy, unsubstituted C2-2o-cycloalkoxy, unsubstituted-C6-2o-aryl, unsubstituted-C ₆ -2o-aryloxy, -OH, -CN, -NR ^a R ^b , -COOR ^a , -CONR ^a R ^b and -CF ₃ . R ^a and R ^b are as defined above. In another embodiment, one of R33 and R34 and one of R35 and R36 together with the carbon atoms to which they are bound form an unsubstituted C3-2o-cycloalkyl or substituted C3-20- cycloalkyl. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, unsubstituted Ci-20-alkoxy, unsubstituted C2-2o-cycloalkoxy, unsubstituted-C6-2o-aryl, unsubstituted-C6-2o-aryloxy, - OH, -CN, -NR ^a R ^b , -COOR ^a , -CONR ^a R ^b and -CF ₃ . R ^a and R ^b are as defined above.

In yet another embodiment, one of R33 and R34 and one of R35 and R36 together with the carbon atoms to which they are bound form an unsubstituted Cs-io-cycloalkyl or substituted Cs-io-cycloalkyl. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, unsubstituted Ci- 20-alkoxy, unsubstituted C2-2o-cycloalkoxy, unsubstituted-C6-2o-aryl, unsubstituted-C6-2o- aryloxy and -OH.

In another embodiment, R33 and R34 together with the carbon atom to which they are bound and/or R35 and R36 together with the carbon atom to which they are bound form an unsubstituted Cs-io-cycloalkyl or substituted Cs-io-cycloalkyl. The substituents may be selected from the group consisting of one or more unsubstituted Ci-20-alkyl, unsubstituted C3-2o-cycloalkyl, unsubstituted Ci-20-alkoxy, unsubstituted C2-2o-cycloalkoxy, unsubstituted-C6-2o-aryl, unsubstituted-C6-2o-aryloxy and -OH.

For the ligand of formula (4), R ₄ i and R42 may be independently selected from the groups described above for Rn and R12. The integer x may be 1 or 2. In one embodiment, the integer x is 1. In this instance, the

side chain of the ligand of formula (9) is . In another embodiment, the integer x

is 2, in which case, the side chain of the ligand (9) is . When the integer x is 2, each R43 may be the same or different and each R ₄₄ may be the same or different.

R43 and R44 may be the same or different. When R43 and R ₄₄ are different, the ligand (4) will contain one or two chiral centres. The ligand (4) can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (4) may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (4). The or each R43 and R ₄₄ may be independently selected from the groups as described above for R13 and Ri ₄ .

R45 may be present or absent. When absent, y is 0. When R45 is present, y may be 1, 2 or 3. When y is 2 or 3, each R45 may be the same or different to each other. The or each R45 may be selected from the groups described above for R15. In one preferred embodiment, y is 0 i.e. R45 is absent.

In one preferred embodiment, the ligand (4) may be

For the ligand of formula (5), R51 and R52 may be independently selected from the groups described above for Rn and R12.

The integer z may be 1 or 2. In one embodiment, the integer z is 1. In this instance, the

side chain of the ligand of formula (5) is . In another embodiment, the integer is 2, in which case, the side chain of the ligand (5) is When the integer z is

2, each R53 may be the same or different and each R54 may be the same or different.

R53 and R54 may be the same or different. When R53 and R54 are different, the ligand (5) will contain one or two chiral centres. The ligand (5) can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (5) may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (5). The or each R53 and R54 may be independently selected from the groups as described above for R13 and R14.

R55 may be present or absent. When absent, the integer "a l" is 0. When R55 is present, "a l" may be 1, 2 or 3. When "a l" is 2 or 3, each R55 may be the same or different to each other. The or each R55 may be selected from the groups described above for R15. In one preferred embodiment, "a l" is 0 i.e. R55 is absent.

In one preferred embodiment, the ligand (5) may be:

In one embodiment, the [M (Y) ₂ (L ¹ )™' (L ² )] complex may be selected from the group consisting of:

[Ru (OAc) ₂ (dppp) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (dppb) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (dppf) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (DCyPFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM);

[Ru (OAc) ₂ (DiPFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (DB'PFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (DPEPhos) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH2, or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (dppm) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Ru (OAc) ₂ (dppe) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (dppp) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (dppb) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM);

[Os (OAc) ₂ (dppf) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (DCyPFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (DiPFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (DB'PFc) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); [Os (OAc) ₂ (DPEPhos) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM);

[Os (OAc) ₂ (dppm) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM); and [Os (OAc) ₂ (dppe) L ² ], where L ² is EN, AMPY, 2-(aminomethyl)-6-(4- methylphenyl)pyridine, quinoline-8-NH ₂ , or 2-(aminomethyl)pyrimidine (AMPYRIM).

In another embodiment, the [M (Y) ₂ (L ¹ )™- (L ² )] complex may be selected from the group consisting of:

[Ru Cl ₂ (dppp) AMPY];

[Ru Cl ₂ (dppb) AMPY];

[Ru Cl ₂ (dppf) AMPY];

[Ru Cl ₂ (DCyPFc) AMPY];

[Ru Cl ₂ (DiPFc) AMPY];

[Ru Cl ₂ (DB'PFc) AMPY].

[Os Cl ₂ (dppp) AMPY];

[Os Cl ₂ (dppb) AMPY];

[Os Cl ₂ (dppf) AMPY];

[Os Cl ₂ (DCyPFc) AMPY];

[Os Cl ₂ (DiPFc) AMPY]; and [OS Cl ₂ (DB'PFc) AMPY].

In another embodiment, the [M (Y) ₂ (L ¹ )™- (L ² )] complex may be selected from the group consisting of:

[Ru (OAc) ₂ (dppp) AMPY];

[Ru (OAc) ₂ (dppb) AMPY];

[Ru (OAc) ₂ (dppf) AMPY];

[Ru (OAc) ₂ (dppf) EN];

[Ru (OAc) ₂ (BINAP) AMPY];

[Ru (OAc) ₂ (dppb) (quinoline-8-NH ₂ )];

[Ru (OAc) ₂ (DPEPhos) AMPY];

[Ru (OAc) ₂ (dppb) AMPYRIM];

[Ru (OAc) ₂ (dppp) AMPYRIM];

[Ru (OAc) ₂ (dppf) AMPYRIM];

[Ru (OAc) ₂ (dppm) AMPY];

[Ru (OAc) ₂ (dppm) EN];

[Ru (OAc) ₂ (dppm) AMPYRIM].

The complex of formula (I) may be prepared according to the processes described in WO2015/079207 and WO2016/193762 (both to Johnson Matthey PLC).

The hydrogenation catalyst may be a complex of formula (II) :

[M Y (L ¹ )™- (L ³ )] (II) wherein :

M is iron, ruthenium or osmium;

Y is an anionic ligand;

L ¹ is a monodentate phosphorus ligand, or a bidentate phosphorus ligand;

m' is 1 or 2, wherein,

when m' is 1, L ¹ is a bidentate phosphorus ligand;

when m' is 2, each L ¹ is a monodentate phosphorus ligand; and

L ³ is a tridentate CNN ligand, for example, of formulae (6'), (7'), (8') or (9') :

The ligands (6), (7), (8) and (9) orthometallate in the presence of a suitable transition metal atom M (e.g . Fe, Ru or Os) to form a transition metal complexes comprising CNN- tridentate ligands (6'), (7'), (8') and (9') in the presence of a suitable base and when the depicted hydrogen atoms are present. The ligands are tridentate as they coordinate through the amino and nitrogen-containing heteroaryl functiona l groups, as well as through the carbon-metal bond created by orthometallation .

(8) (9)

For the ligand of formula (7), R ₇ _ and R72 may be independently selected from the groups described above for Rn and R12.

The integer h may be 1 or 2. In one embodiment, the inte er h is 1. In this instance, the

side chain of the ligand of formula (7') is bodiment, the integer

h is 2, in which case, the side chain of the ligand (7') is . When the integer h is 2, each R73 may be the same or different and each R ₇₄ may be the same or different.

R73 and R74 may be the same or different. When R73 and R7 ₄ are different, the ligand (7') will contain one or two chiral centres. The ligand (7') can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (7') may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (7'). The or each R73 and R7 ₄ may be independently selected from the groups as described above for R13 and Ri ₄ .

The integer i may be 0 or 1. In one embodiment, i is 0, in which case the nitrogen- containing aromatic ring is a pyrrolyl ring. In another embodiment, i is 1. In this instance, the nitrogen-containing aromatic ring is a pyridinyl ring.

R75 may be present or absent. When absent, i is 0 i.e. the pyrrolyl or pyridinyl ring is not substituted. When i is 0, j may be 1 (i.e. the pyrrolyl ring may have one R55 group). When i is 1, j may be 1 or 2 (i.e. the pyridinyl ring may have one or two R55 groups). When j is 1 or where appropriate 2, each R75 may be the same or different to each other. The or each R75 may be selected from the groups described above for R15. Preferably, j is 0 i.e. R75 is absent. R76 may be present or absent. When absent, k is 0. When R ₇ 6 is present, k may be 1 or 2. When k is 2, each R ₇ 6 may be the same or different to each other. The or each R ₇ 6 may be selected from the groups described above for R15. In one preferred embodiment, k is 0 i.e. R76 is absent.

R77 may be present or absent. When absent, I is 0. When R77 is present, I may be 1, 2, 3 or 4. When I is 2, 3 or 4, each R77 may be the same or different to each other. The or each R77 may be selected from the groups described above for R15. In one preferred embodiment, I is 0 i.e. R77 is absent.

In one preferred embodiment, the bidentate Ν,Ν-ligand (6') is selected from the group consisting of:

In one preferred embodiment, the bidentate Ν,Ν-ligand (7') is selected from the consisting of:



In one particularly preferred embodiment, the bidentate Ν,Ν-ligand is 1- benzo[/7]quinoline-2-yl-methanamine (AMBQ).

For the ligand of formula (8'), Rsi and Rs2 may be independently selected from the groups described above for Rn and R12.

The integer r may be 1 or 2. In one embodiment, the integer r is 1. In this instance, the

side chain of the ligand of formula (6) is . In odiment, the integer r

is 2, in which case, the side chain of the ligand (6) is when the integer r is 2, each Rs3 may be the same or different and each Rs ₄ may be the same or different. Rs3 and R8 ₄ may be the same or different. When Rs3 and Rs ₄ are different, the ligand (8') will contain one or two chiral centres. The ligand (8') can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (8') may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (8')- The or each Rs3 and Rs ₄ may be independently selected from the groups as described above for R13 and Ri ₄ .

Rs5 may be selected from -H or the groups as described above for R15. f½5 may be present or absent. When absent, s is 0. When Rs6 is present, s may be 1 or 2. When s is 2, each Rs6 may be the same or different to each other. The or each Rs6 may be selected from the groups described above for R15. In one preferred embodiment, s is 0 i.e. Rs6 is absent.

Rs7 may be present or absent. When absent, t is 0. When Rs7 is present, t may be 1, 2, 3 or 4. When t is 2, 3 or 4, each Rs7 may be the same or different to each other. The or each Rs7 may be selected from the groups described above for R15. In one preferred embodiment, t is 0 i.e. Rs7 is absent.

In one preferred embodiment, the ligand (8') may be:

For the ligand of formula (9'), R91 and R92 may be independently selected from the groups described above for Rn and R12.

The integer u may be 1 or 2. In one embodiment, the integer u is 1. In this instance, the

side chain of the ligand of formula (9') is . In another embodiment, the integer

u is 2, in which case, the side chain of the ligand (9') is . when the integer u is 2, each R93 may be the same or different and each R94 may be the same or different.

R93 and R94 may be the same or different. When R93 and R94 are different, the ligand (9') will contain one or two chiral centres. The ligand (9') can be used as a racemic mixture, as either single enantiomer, as any single diastereomer, as a mixture of enantiomers, or as a mixture of diastereomers, preferably as a single enantiomer. The enantiomers or diastereomers of ligand (9') may be obtained in enantiomerically pure form by resolution of e.g. a racemic mixture of ligand (9')- The or each R93 and R94 may be independently selected from the groups as described above for R13 and R14. R95 may be selected from -H or the groups as described above for R15.

R96 may be present or absent. When absent, v is 0. When R96 is present, v may be 1 or 2. When v is 2, each R96 may be the same or different to each other. The or each R96 may be selected from the groups described above for R15. In one preferred embodiment, v is 0 i.e. R96 is absent.

R97 may be present or absent. When absent, w is 0. When R97 is present, w may be 1, 2, 3 or 4. When w is 2, 3 or 4, each R97 may be the same or different to each other. The or each R97 may be selected from the groups described above for R15. In one preferred embodiment, w is 0 i.e. R97 is absent.

In one preferred embodiment, the ligand (9') may be:

M is iron, ruthenium or osmium. In one embodiment, M is ruthenium or osmium. L ¹ is a monodentate phosphorus ligand, or a bidentate phosphorus ligand as described above for the complexes of formula (I).

The complex of formula (II) may be prepared according to the processes described in WO2015/079207 and WO2016/193762 (both to Johnson Matthey PLC).

The hydrogenation catalyst may be a complex of Formula III or IV: wherein :

each Z is simultaneously or independently a hydrogen or halogen atom, a C1-C6 alkyl, a carbene group, a hydroxyl group, or a C1-C7 alkoxy radical, a nitrosyl (NO) group, CO, CNR (R=Alkyl, Aryl), nitrile, phosphite, phosphinite, or phosphine such as PMe3 or PP ; M is Fe, Ru or Os;

p is equal to 1 or 2, whereas pi is equal to 1, 2, or 3;

SN and SNS are coordinated ligands of any one of Formulae IA or IB:

where

SR ¹ is a thioether group, which is coordinated to the metal centre of the catalyst or pre- catalyst;

the dotted lines simultaneously or independently indicate single or double bonds;

R ¹ , R ² , R ⁵ , and R ⁶ are each independently H, a substituted or unsubstituted linear or branched C1-C20 alkyl (such as Ci-Cs alkyl), a substituted or unsubstituted cyclic C3-C8 alkyl, or a substituted or unsubstituted C2-C20 alkenyl, a substituted or unsubstituted C5- C20 aryl (such as a C5-C14 or C5-C8 aryl), -OR or -N R2; or when taken together, R ¹ and R ² group or R ⁵ and R ⁶ groups can form a saturated or partially saturated C5-C20 cycle;

R ³ and R ⁴ are each independently H, a substituted or unsubstituted linear, branched or cyclic Ci-Cs alkyl or alkenyl, a substituted or unsubstituted C5-C8 aromatic group, ester group; or, when taken together, R ³ and R ⁴ can form an optionally substituted saturated or partially saturated C5-C20 hetero-aromatic ring;

R ⁵ when taken together with R ⁴ can form an optionally substituted saturated or partially saturated C5-C20 aromatic ring;

R ⁷ is H, a substituted or unsubstituted linear or branched Ci-Cs alkyl (such as a Ci-Cs alkyl), a substituted or unsubstituted cyclic C3-C8 alkyl, a substituted or unsubstituted C2- C20 alkenyl, or a substituted or unsubstituted C5-C20 aryl (such as a C5-C14 or C5-C8 aryl); and

n, m, and q are simultaneously or independently 0, 1 or 2. M is Fe, Ru or Os. In one embodiment, M is Ru or Os. The coordinating groups of the tridentate SNS ligand consist of two thioether groups and one nitrogen (amino) group. The coordinating groups of the bidentate SN ligand consist of one thioether and one nitrogen (amino) group. The complexes of formulae III and IV may exist in both neutral or cationic forms.

The metal complex of Formula IV may be selected from the group:

a) RuCl2(PPh3)[(EtSC ₂ H ₄ )2NH];

b) RuHCI(PPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH];

c) RuCI ₂ (AsPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH];

d) RuHCI(CO)[(EtSC ₂ H ₄ ) ₂ NH];

e) RuH(OEt)(PPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH]-EtOH; or

f) RuH ₂ (PPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH].

The metal complex of Formula IV may be selected from the group:

a) OsCI ₂ (PPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH];

b) OsHCI(PPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH];

c) OsCI ₂ (AsPh ₃ )[(EtSC ₂ H ₄ ) ₂ NH]; and

d) OsHCI(CO)[(EtSC ₂ H ₄ ) ₂ NH].

In one embodiment, the complex of formula IV may have the following structu

or the corresponding complex in which Ru is replaced with Os.

The SN and SNS ligands, as well as the complexes of formulae III and IV may be prepared according to the procedures described in WO2014/036650 (to Goussev eta/).

The hydrogenation catalyst may be a complex of Formula V or VI: wherein:

each Z' is independently a hydrogen or halogen atom, a Ci-Ce alkyl, a hydroxyl, or a Ci- C6 alkoxy, a nitrosyl (NO) group, CO, CNR, or PR ₃ , wherein R is an alkyl or an aryl (such as PMe ₃ or PPh ₃ );

M is Fe, Ru or Os; q l is 2 or 3; and

each LNN' is a coordinated ligand that is a compound of Formula VII :

wherein

L is a phosphine (PR ^la R ^2a ), a sulfide (SR ^la ), or a carbene group (CR ^la );

each Y' is independently a C, N or S atom, wherein at least two Y's are C;

the dotted lines simultaneously or independently represent single or double bonds, wherein when a single bond is present the carbon atom or atoms bound to R ^4a , R ^5a or both, are additionally bound to an H;

R ^la and R ^2a are each independently H, or a C1-C20 linear alkyl, a C3-C20 branched alkyl, a

C3-C8 cycloalkyl, a C2-C8 alkenyl, a C5-C20 aryl, each of which may be optionally substituted, or -OR' or -NR'2; or when taken together, R ^la and R ^2a can together with L to which they are bound form a saturated or partially saturated ring;

R ^3a is H, or a Ci-Cs linear alkyl, a C3-C8 branched alkyl, a C3-C8 cyclic alkyl, a C2-C8 alkenyl, or a C5-C8 aryl, each of which may be optionally substituted;

R ^4a is H, a C3-C8 linear alkyl, C3-C8 cyclic alkyl, a C2-C8 alkenyl, or a C5-C8 aryl, each of which may be optionally substituted;

or R ^3a and R ^4a can join together to form a saturated heterocycle;

R ^5a is H, a linear Ci-Cs alkyl, a branched C3-C8 alkyl, a cyclic C3-C8 alkyl, a C2-C8 alkenyl, or a C5-C8 aryl, each of which can be optionally substituted; or R ^5a and R ^4a can join together to form a saturated heterocycle;

each X' is independently H, a linear Ci-Cs alkyl, a branched C3-C8 alkyl, a cyclic C3-C8 alkyl, a C2-C8 alkenyl, or a C5-C8 aryl, each of which can be optionally substituted, or OR', F, CI, Br, I or NR'2; or when taken together, two of the X' groups can together form an optionally substituted saturated ring, partially saturated ring, aromatic ring, or heteroaromatic ring;

R' is H, a C1-C20 linear alkyl, a C3-C20 branched alkyl, a C3-C8 cycloalkyl, a C2-C8 alkenyl, or a C5-C8 aryl, each of which may be optionally substituted;

each nl and ml is independently 1 or 2; kl is 1 or 2; and

zl is 0 or 1.

M is Fe, Ru or Os. In one embodiment, M is Ru or Os.

In one embodiment, R ^3a is H, or Ci-Cs linear alkyi, C3-C8 branched alkyi, cyclic alkyi C3- Cs, C2-C8 alkenyl, C5-C8 aryl, each of which may be optionally substituted;

R ^4a is H a C3-C8 linear alkyi, C3-C8 cyclic alkyi, a C2-C8 alkenyl, or a C5-C8 aryl, each of which may be optionally substituted; and

R ^5a is H, a linear Ci-Cs alkyi, branched C3-C8 alkyi, cyclic C3-C8 alkyi, C3-C8 alkenyl, or C5- Cs aryl, each of which can be optionally substituted.

In the compound of formula (I), R ^4a and R ^5a may both be H. In the compound of formula (VII), each Y' may be C.

In the compound of formula (VII), kl may be 2, and each X' may be H.

In the compound of formula (VII), L may be PR ^la R ^2a .

The compound of Formula VII may be selected from the group:

The complex of formula (V) or (VI) may be selected from the group

The complex of formula (V) or (VI) may be selected from the group: The PNN' ligand, as well as the complexes of formula (V) and (VI) may be prepared according to the procedures described in WO2013/023307 (to Goussev et a/). Certain aspects and embodiments of the invention will now be described by the way of the following non-limiting Examples.

Examples

Example 1

Cin

under 30 bar pressure of H ₂ . Ru-SNS = RuCl2(PPh3)[(EtSC ₂ H ₄ )2NH].

* Comparative experiments.

Experimental Method:

A reaction vial is charged with catalyst (0.001-0.002 mmol, S/C 10,000/1 - 20,000/1) and 1 or 5 vol% H2O (50 μΙ or 250 μΙ) was added directly onto the catalyst before the vials were loaded into the Biotage Endeavour and purged with N ₂ (g) five times (until 3 bar then pressure vented). Trans-cinnamaldehyde substrate (2.5 ml, 20 mmol) was injected into the vials. KOEt base (5 mol%, 0.4 ml, 24% wt. solution in EtOH) was injected into each vial. Me-THF solvent (1.9ml_, to make a 4.0 M substrate concentration) was injected into each vial. The vials were purged with N ₂ (g) five times (until 3 bar then pressure vented) without stirring and five times with stirring turned on. Then the reaction vials were purged with H ₂ (g) five times (until 20 bar then pressure vented) with stirring. The pressure was set at 30 bar and the temperature was heated to 40 °C with stirring (600 rpm). After 16 hours, the reaction vials were allowed to cool to room temperature before the pressure was released and they were purged with N ₂ (g) five times with stirring. Samples were diluted with EtOH and analysed by GC.

Ru-SNS Catalysts

• Ru-SNS was shown to be an active catalyst for cinnamaldehyde hydrogenation (with up to 100% selectivity for the cinnamyl unsaturated alcohol).

• The highest conversion obtained was 96% (with 1% S.M . and 3% benzyl alcohol) at a loading of S/C 20,000/1 - with no observable saturated alcohol. This was obtained in the presence of 5 vol% H ₂ 0 (and 5 mol% KOEt) which was shown to help with increasing the conversions.

• The advantageous effect of H ₂ 0 was most noticeable at lower loadings. At S/C 10,000/1, adding 5 vol% H ₂ 0 increased the conversion from 5% to 95%.

• KOH (as a solution in EtOH) was found to be effective as an alternative base to KOEt (in EtOH) - giving very similar results at S/C 5000/1.

• A few other catalysts were compared to Ru-SNS. Ru-PNN gave similar results to Ru-SNS (tested at S/C 5000/1 with KOH base, S/C 5000/1 with KOEt base and at S/C 10,000/1 with KOEt base).

• Methyl and ethyl cinnamate esters were tested as alternative starting materials of which both gave lower conversions, poorer selectivity and longer reaction times. They were also tested in the presence of H2O in which no hydrogenation reaction occurred.

Ru-AMPY Catalysts

· [dppf Ru CI2 AMPY] and [dppb Ru Cl ₂ AMPY] were also tested under these conditions, [dppb Ru CI2 AMPY] gave low conversions particularly when in the absence of any H2O (H2O shown to also be advantageous for these catalysts), [dppf Ru Cl ₂ AMPY] gave >90% conversions. Other Noyori-Type Catalysts

• The effect of H2O for cinnamaldehyde was again seen to very significant, tested using another catalyst, (P P^RuC EN, - with a large increase in conversion (from 17% to 77%). This catalyst is however not as selective as Ru-SNS has been shown to be - with 15% of the saturated alcohol present.

Example 2

Furfuryl aldehyde

Ru-SNS was tested on another substrate: furfural. Furfural is obtained from sugars from biomass and furfuryl alcohol is used in many applications such as solvents, plastics, resins and adhesives.

Hydrogenation of furfural to furfuryl alcohol. A range of conditions were tested on furfural in the Biotage Endeavour hydrogenator using a Ru-SNS stock solution to achieve the low loadings on this scale.

• The results showed that S/C 100,000/1 can achieve full conversion in 5 hours (compared to S/C 50,000/1 in 1 hour).

• 5 mol% and 1 mol% (with 1 vol% H ₂ 0 also added) of the KOEt base both gave >99% of product therefore showing that less than 10 mol% base can be used for full conversion.

Entry Ru-SNS Base H2O Added Time for % % Loading H ₂ Product Others (S/C) uptake

(~h) a 50,000/1 KOEt (10 mol%) - 0.5 0 89 11

2* _' ^a 50,000/1 KOEt (1 mol%) - 25 31 69 0

3*' ^a 50,000/1 KOEt (1 mol%) + 16 31 69 0

EtOH

₄ b 20,000/1 KOEt (10 mol%) 1 vol% 1 0 100 0

5 ^b 20,000/1 KOEt (20 mol%) 1 vol% n/d 1 99 0

6 ^b 50,000/1 KOH(aq) (1 mol%) (10 vol%) ^c 15 29.8 70.2 0.0

7 ^b 50,000/1 KOEt (10 mol%) 1 vol% 1 0.4 99.6 0.0

8 ^b 50,000/1 KOEt (1 mol%) 1 vol% 5 0.1 99.9 0.0

Table 1 : Testing a range of loadings and bases for furfural hydrogenation, at 40 °C, 30 bar H2, 16 hours. ^{2 a} see below for method ^b see below for method ^c approximate % volume of water when using aqueous KOH solution. Ru-SNS = RuCl2(PPh ₃ ) [(EtSC2H ₄ )2N H ] .

* Comparative experiment ^a METHOD: A 25 ml Parr Vessel was loaded with Ru-SNS (1.5 mg, S/C 50,000/1) and the reaction vessel was purged with N2 (g) five times. Furfural substrate (> 98% purity, 120 mmol, 10.2 ml) followed by KOEt base (1 or 10 mol%, 0.5 ml or 4.8 ml respectively) was then injected into the vessel. EtOH (4.0 ml) was also added for entry 3. The vessel was purged with N2 (g) five times with stirring off and five times with stirring set to half maximum speed. The stirring was then stopped and the vessel was purged with H2 (g) to 10 bar five times. The stirring was turned on to half the maximum speed again and purged five times more with H2 (g). Then the stirring was set to maximum speed and the temperature set to 40 °C (slowly, to not overshoot the temperature) and the programme was set to record the H2 consumption. At the end of the reaction, the vessel was allowed to cool to room temperature before being purged with N2 (g) five times. A sample in IPA was taken for the GC analysis. ^b METHOD: A stock solution of Ru-SNS catalyst was made (3.0 mg in 1 ml DCM). Appropriate volumes of the solution were added to each reaction vial (210 μΙ for S/C 20,000/1, 84 μΙ for S/C 50,000/1 and 42 μΙ for S/C 100,000/1) and the DCM solvent was blown off with N2. H2O (50 μΙ, 1 vol%) was added to the relevant vials where indicated in the table before they were loaded into the Biotage Endeavour and purged with N2 (g) five times (until 3 bar then pressure vented). Furfural (> 98% purity, 1.7 ml, 20 mmol) was injected into each vial followed by KOEt (24% wt. solution in EtOH) or KOH ( IN aqueous solution) base. EtOH solvent (making a 4.0 M substrate concentration) was added to each vial. The vials were purged with N ₂ (g) five times (until 3 bar then pressure vented) without stirring and five times with stirring turned on. Then the reaction vials were purged with H ₂ (g) five times (until 20 bar then pressure vented) with stirring. The pressure was set at 30 bar and the temperature was heated to 40 °C for 16 hours with stirring (600 rpm). After 16 hours, the reaction vials were allowed to cool to room temperature before the pressure was released and they were purged with N ₂ (g) five times with stirring. Samples were diluted with IPA and analysed by GC.

Example 3

Benzylideneacetone:

a) Conditions: 5% NaOEt (21% wt in EtOH), MeTHF (1 vol), 40°C reaction run for 16 h under 30 bar pressure of H ₂ ; b) C=0 vs C=C; c) unsaturated product confirmed by ^X H NMR following filtration through AI2O3 (eluting with MTBE) and removal of solvents.

Experimental Method: A reaction vial is charged with catalyst (0.001 mmol, S/C 10,000/1) and 5 vol% H ₂ 0 (150 μΙ) was added directly onto the catalyst. Followed by a solution of substrate (10 mmol) in Me-THF (1.5ml_). The base is then added (NaOEt base (5 mol%, 0.187 ml, 21% wt. solution in EtOH). The vials were loaded into the Biotage Endeavour and purged with N ₂ (g) five times (until 3 bar then pressure vented) and a further five times with stirring turned on. Then the reaction vials were purged with H ₂ (g) five times (until 30 bar then pressure vented) with stirring. The pressure was set at 30 bar and the temperature was heated to 40 °C with stirring (600 rpm). After 16 hours, the reaction vials were allowed to cool to room temperature before the pressure was released and they were purged with N ₂ (g) five times with stirring. Samples were diluted with iPrOH and analysed by GC.

Example 4

3-Octen-2-one:

a) Conditions: 5% NaOEt (21% wt in EtOH), MeTHF (1-3 vol), 40°C reaction run for 24 under 30 bar pressure of H ₂ ; b) C=0 vs C=C; c) unsaturated product confirmed by ^X H NMR following filtration through AI2O3 (eluting with MTBE) and removal of solvents.

Experimental Method:

A reaction vial is charged with catalyst (0.001 mmol, S/C 10,000/1) and 2.5-5 vol% H ₂ 0 (150 μΙ) was added directly onto the catalyst. Followed by substrate (10 mmol) and MeTHF (1.5-4.5 ml_, 1-3 vol). The base is then added (NaOEt base (5 mol%, 0.187 ml, 21% wt. solution in EtOH). The vials were loaded into the Biotage Endeavour and purged with N ₂ (g) five times (until 3 bar then pressure vented) and a further five times with stirring turned on. Then the reaction vials were purged with H ₂ (g) five times (until 30 bar then pressure vented) with stirring. The pressure was set at 30 bar and the temperature was heated to 40 °C with stirring (600 rpm). After 16 hours, the reaction vials were allowed to cool to room temperature before the pressure was released and they were purged with N ₂ (g) five times with stirring. Samples were diluted with iPrOH and analysed by GC.