GRAINGER DAMIAN (GB)
| WO2014036650A1 | 2014-03-13 | |||
| WO2015110515A1 | 2015-07-30 | |||
| WO2016202925A1 | 2016-12-22 |
| Claims 1. 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 a solvent, wherein the solvent is essentially free of water, and : (a) the hydrogenation catalyst is a complex of Formula (III) or (IV) : M(SNS)Za 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 a is equal to 1, 2, or 3; SN and SNS are coordinated ligands of any one of Formulae IA or IB: where SR1 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; R1, R2, R5, and R6 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 -NR2; or when taken together, R1 and R2 group or R5 and R6 groups can form a saturated or partially saturated C5-C20 cycle; R3 and R4 are each independently H, a substituted or unsubstituted linear, branched or cyclic Ci-Cs alkyl or alkenyl, a substituted or unsubstituted C5- Cs aromatic group, ester group; or, when taken together, R3 and R4 can form an optionally substituted saturated or partially saturated C5-C20 hetero- aromatic ring; R5 when taken together with R4 can form an optionally substituted saturated or partially saturated C5-C20 aromatic ring; R7 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; or (b) the hydrogenation catalyst is a complex of Formula V or VI: [M(LNN')Z'b] (V) μΛ/[Μ(ίΝΝ')Ζ^]2 (VI) wherein : each Z' is independently a hydrogen or halogen atom, a C1-C6 alkyl, a hydroxyl, or a C1-C6 alkoxy, a nitrosyl (NO) group, CO, CNR, or PR3, wherein R is an alkyl or an aryl (such as PMe3 or PP ); M is Fe, Ru or Os; b is 2 or 3; and each LNN' is a coordinated ligand that is a compound of Formula I: I wherein L is a phosphine (PRlaR2a), a sulfide (SRla), or a carbene group (CRla); 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 R4a, R5a or both, are additionally bound to an H; Rla and R2a 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 -NR2; or when taken together, Rla and R2a can together with L to which they are bound form a saturated or partially saturated ring; R3a 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; R4a 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 R3a and R4a can join together to form a saturated heterocycle; R5a 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 R5 and R4 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 NR2; 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 n and m is independently 1 or 2; kl is 1 or 2; and zl is 0 or 1. A process according to claim 1, wherein the compound comprising an α,β- unsaturated carbonyl group is a compound of formula (A) and the compound comprising an allyl alcohol group is a compound of formula (Α'): (A) (Α') 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-C15- cycloalkyl, substituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5- C2o-aryl, unsubstituted C4-C2o-heteroaryl, substituted C4-C2o-heteroaryl, wherein the heteroatoms in the C4-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen; or one or more pairs selected from Ra/Rb, Rb/Rc, Rc/Rd or Ra/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. A process according to claim 1, wherein the compound comprising an α,β- unsaturated carbonyl group is a compound of formula (B) and the compound comprising an allyl alcohol group is a compound of formula (Β'): wherein: X is an oxygen atom, a sulfur atom or an -N(Re)- group; Ra, Rb, Rc, Rd and Re are independently selected from the group consisting of H, unsubstituted Ci-C2o-alkyl, substituted Ci-C2o-alkyl, unsubstituted C3-C15- cycloalkyl, substituted C3-Ci5-cycloalkyl, unsubstituted C5-C2o-aryl, substituted C5- C2o-aryl, unsubstituted C4-C2o-heteroaryl, substituted C4-C2o-heteroaryl, wherein the heteroatoms in the C4-C2o-heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen; or one or more pairs selected from Ra/Re, Re/Rb, Rb/Rc, Rc/Rd or Ra/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. A process according to any one of the preceding claims, wherein the inorganic base is selected from a hydroxide, alkoxide, carbonate, acetate or phosphate. A process according to any one of the preceding claims, wherein the substrate/catalyst (S/C) molar ratio of the compound comprising an α,β- unsaturated carbonyl group to hydrogenation catalyst is in the range of about 100 : 1 to about 200,000: 1. A process according to claim 9, wherein the substrate/catalyst (S/C) ratio is in the range of > about 5,000 : 1 to < about 100,000: 1. A process according to any one of the preceding claims, wherein the solvent is selected from the group consisting of alcoholic solvents, cyclic ether solvents, aromatic solvent, alkane solvents, and a mixture thereof. A process according to any preceding claim, wherein the hydrogenation is carried out at one or more temperatures in the range of > about 20 °C to about < about 100 °C. |
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 a solvent, wherein the solvent is essentially free of water, and the hydrogenation catalyst is a complex of Formula (III), (IV), (V) or (VI) as described below.
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 :
R a , R b , R c and R d 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 C4-C20- heteroaryl, substituted C4-C2o-heteroaryl, wherein the heteroatoms in the C4-C20- heteroaryl are selected from the group consisting of sulfur, oxygen and nitrogen; or one or more pairs selected from R a /R b , R b /R c , R c /R d or R a /R d 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. R a , R b , R c and R d 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, R a , R b , R c and R d are independently selected from -H and phenyl. In one embodiment, compound (A) is cinnamaldehyde (i.e. R a and R b are -H, one of R c and R d is phenyl and the other of R c and R d is -H). Compound (A) is a cyclic α,β-unsaturated ketone when R a is linked to form a ring structure with R b . In this instance, R c and R d may be independently selected from the groups defined above or R c may be linked to form a ring structure with R d . Compound (A) is also a cyclic α,β-unsaturated ketone when R a is linked to form a ring structure with R d . In this instance, R b and R c may be independently selected from the groups defined above or R b may be linked to form a ring structure with R c .
When R b is linked to form a ring structure with R c , R a and R d may be independently selected from the groups defined above or R a may be linked to form a ring structure with R d . When R c is linked to form a ring structure with R d , R a and R b may be independently selected from the groups defined above.
The pairs R a /R b , R b /R c , R c /R d or R a /R d 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;
R a , R b , R c , R d 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-heteroa ryl, 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 , R e /R b , R b /R c , R c /R d or R a /R d 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 a n 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.
R a , R b , R c , R d 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, R a , R b , R c , R d and R e are -H. In one embodiment, compound (B) is furfuryl aldehyde (i.e. X is an oxygen atom and R a , R b , R c , R d 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, R b , R c and R d may be independently selected from the groups defined above or R b may be linked to form a ring structure with R c , or R c may be linked to form a ring structure with R d .
Compound (B) is also a cyclic α,β-unsaturated ketone when R a is linked to form a ring structure with R d . In this instance, R e (if present), R b and R c may be independently selected from the groups defined above or R b 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 R b .
When R b is linked to form a ring structure with R c , R e (if present), R a and R d may be independently selected from the groups defined above or R a may be linked to form a ring structure with R d , or R e (if present) may be linked to form a ring structure with R a . When R c is linked to form a ring structure with R d , R e (if present), R a and R b 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 R b .
The pairs R a /R e , R e /R b , R b /R c , R c /R d or R a /R d 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 , R b , R c , R d , and the pairs R a /R b , R b /R c , R c /R d and R a /R d are as defined above. The compound of formula (B) may be reduced to a compound of formula (Β') :
(B) (Β')
wherein R a , R b , R c , R d , X and the pairs R a /R b , R b /R c , R c /R d and R a /R d are as defined above. The hvdroqenation reaction
Hydrogenation is the addition of molecular hydrogen gas (H2) 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 a 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 process is carried out in a solvent which is essentially free of water. A solvent which is "essentially free of water" is one which contains water only as an unavoidable impurity. In one embodiment, the solvent is anhydrous. The solvent may be selected from the group consisting of alcoholic solvents, cyclic ether solvents, aromatic solvents, alkane solvents, and a mixture thereof. Examples of alcoholic solvents include but are not limited to methanol, ethanol, propanol (n- or i-) and butanol (n-, i- or t-). Examples of cyclic ether solvents include but are not limited to tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (MeTHF), 3- methyl -tetrahydrofuran and 1,4-dioxane. 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. The molar concentration of the starting material substrate in the solvent may be between about 0.1- 10 M, such as about 3-9 M, for example, about 4-8M.
The process may 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 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 solvent 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 or 65 °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 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. Hvdroqenation catalyst
The hydrogenation catalyst is a complex of Formula (III), (IV), (V) or (VI). The hydrogenation catalyst may be a complex of Formula III or IV:
M (SNS)Z a 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 a is equal to 1, 2, or 3;
SN and SNS are coordinated ligands of any one of Formulae IA or IB:
Forstoi& A formula 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 alkyi (such as a Ci-Cs alkyi), a substituted or unsubstituted cyclic C3-C8 alkyi, 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) RuCl2(AsPh 3 )[(EtSC 2 H 4 )2NH] ;
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 ) [(EtSC2H 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 structure:
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 et a/).
The hydrogenation catalyst may be a complex of Formula V or VI :
[M(LNN')Z' b ] (V)
M w [M(LNN')Z'b] 2 (VI) wherein :
each Z' is independently a hydrogen or halogen atom, a C1-C6 alkyl, a hydroxyl, or a Ci- C6 alkoxy, a nitrosyl (NO) group, CO, CNR, or PR3, wherein R is an alkyl or an aryl (such as PMe 3 or PPh 3 );
M is Fe, Ru or Os;
b is 2 or 3; and
each LNN' is a coordinated ligand that is a compound of Formula I:
I 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 41 , R 51 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 -NR2; 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 5 and R 4 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 N R2; 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 31 is H, or Ci-Cs linear alkyl, C3-C8 branched alkyl, cyclic alkyl C3- Cs, C2-C8 alkenyl, C5-C8 aryl, each of which may be optionally substituted;
R 41 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; and
R 51 is H, a linear Ci-Cs alkyl, branched C3-C8 alkyl, cyclic C3-C8 alkyl, 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 (I), each Y' may be C.
In the compound of formula (I), kl may be 2, and each X' may be H. In the compound of formula (I), L may be PR la R 2a . The compound of Formula I 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
Cinnamaldehyde:
a) Conditions: 5% KOEt (24% wt in EtOH), MeTHF, 40°C reaction run for 16 h under 30 bar pressure of H 2 .
Experimental Method:
A reaction vial was charged with catalyst (0.001-0.002 mmol, S/C 10,000/1 - 20,000/1) before the vial was 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.
Methyl and ethyl cinnamate esters were tested with Ru-SNS catalysts as alternative starting materials of which both gave lower conversions, poorer selectivity and longer reaction times.
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 lots of applications such as solvents, plastics, resins and adhesives.
Figure 1: Hydrogenation of furfural to furfuryl alcohol. Initial tests were carried out using S/C 10,000/1 and 20,000/1 of Ru-SNS. Two temperatures and two substrate batch purities were also tested. • The GC results showed very high conversions for loadings of S/C 20,000/1 with the lower temperature of 40 °C giving, in general, less impurities.
• The reaction rate was very fast with the reaction reaching completion under 1 hour. Table 1: Testing of hydrogenation of furfural using Ru-SNS catalyst, 30 bar H 2 ,
16 hours. 1
Entry Ru-SNS Substrate [S] KOEt Temperature % % %
Loading Batch Base S.M. Product Others
(S/C) Purity
1 10,000/1 98% 5 M 10 40 °C 0 96 4
mol%
2 20,000/1 98% 5 M 10 40 °C 0 95 5
mol%
3 10,000/1 >98% 5 M 10 40 °C 0 96 4
mol%
4 20,000/1 >98% 5 M 10 40 °C 0 93 7
mol%
5 10,000/1 98% 5 M 10 65 °C 0 92 8
mol%
6 20,000/1 98% 5 M 10 65 °C 0 93 7
mol%
7 10,000/1 >98% 5 M 10 65 °C 0 98 2
mol%
8 20,000/1 >98% 5 M 10 65 °C 0 82 18
mol%
9 2 20,000/1 >98% 4 M 10 40 °C 0.4 99.6 0
mol%
10 2 50,000/1 >98% 4 M 10 40 °C 0.5 99.5 0
mol%
50,000/1 >98% 4 M 5 40 °C 0.3 99.7 0
mol%
12 2 100,000/1 >98% 4 M 10 40 °C 0.2 99.8 0
mol%
13 3 50,000/1 >98% 8 M 10 40 °C 0 89 1 1
mol%
S.M. = starting material.
Ru-SNS = RuCl2(PPh3)[(EtSC 2 H 4 )2NH] . METHOD: The reaction vials were charged with Ru-SNS (1.3 mg and 0.7 mg to make S/C 10,000/1 and 20,000/1 respectively) and loaded into the Biotage Endeavour and purged with N 2 (g) five times (until 3 bar then pressure vented). The two batches of furfural substrate (1.7 ml, 20 mmol) was injected into appropriate vials and KOEt base (10 mol%) was added to each vial. Me-THF solvent (1.5 ml, making a 5.0 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 or 65 °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.
2 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 N 2 . The vials were then loaded into the Biotage Endeavour and purged with N 2 (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). EtOH solvent (making a 4.0 M substrate concentration) was injected into 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.
3 Since the reaction went to completion in a very short time using S/C 20,000/1 - 100,000/1, the reaction was then scaled up to 120 mmol in a Parr Vessel using S/C 50,000/1. Reaction temperature of 40 °C was chosen as and 10 mol% KOEt (24% wt. solution in EtOH) was used. No other solvent was needed for this set-up in the Parr Vessel.
Example 3
Benzylideneacetone:
Ru catalyst Entry Catalyst 3 Loading (S/C) Conv (% GC GG
GC) Selectivity 13 ' 0 purity
(%)
1 Ru-SNS 10,000/1 87.4 >98: 2 21.6
2 Ru-PNN 10,000/1 92.8 >97: 3 46.4
a) Conditions: 5% NaOEt (21% wt in EtOH), MeTHF (1 vol), 40°C reaction run for 16 h under 30 bar pressure of H2; 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) 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) Con itions: Na Et 1 wt in Et H , MeTHF 1- vo , 4 reaction run or 24 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) followed by substrate (10 mmol) and Me-THF (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.