POLYDENTATE LIGANDS AND THEIR COMPLEXES FOR MOLECULAR CATALYSIS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial Nos.

62/136,085, filed March 20, 2015; 62/130,977, filed March 10, 2015; 62/118,386, filed February 19, 2015; and 62/009,483, filed June 9, 2014. The subject matter of each of these applications is incorporated by reference herein in its entirety for all purposes.

STATEMENT REGARDING FEDERAL RIGHTS

[0002] This invention was made with government support under Contract No. DE- AC52-06NA25396 awarded by the U.S. Department of Energy. The government has certain rights in the invention.

FIELD OF THE INVENTION

[0003] The present invention relates generally to polydentate ligands and transition metal complexes of these ligands, some of which are relevant to the area of so-called bifunctional metal-ligand M/NH cooperative molecular catalysis. In particular, the catalysts can be used in a wide range of catalytic reactions, including hydrogenation and transfer hydrogenation of unsaturated organic compounds, dehydrogenation of alcohols and boranes, various

dehydrogenative couplings, catalytic C-N and C-C bond-forming reactions, hydration of nitriles, aerobic oxidative transformation of alcohols into ketones and esters and others.

BACKGROUND OF THE INVENTION

[0004] Progress in homogeneous catalysis including homogeneous hydrogenation often involves the development of new ligands and their transition-metal complexes that are active pre-catalysts or catalysts. The vast majority of ligands used in homogeneous catalysis are based on P and/or N donor atoms and an enormous number of such ligands have been designed and synthesized over the past four decades.

[0005] It is generally accepted that polydentate chelating ligands bearing NH

functionalities play a crucial role in so-called bifunctional metal-ligand (M/NH) cooperative molecular catalysis, in which a non-innocent ligand is proposed to directly participate in substrate activation via an N-H group and/or an act of bond cleavage/formation via N-H proton transfer, respectively. The bifunctional molecular catalysis based on metal-ligand M/NH cooperation was originally developed for asymmetric hydrogenation and transfer hydrogenation of ketones and imines and is now applicable to variety of chemical transformations with a wide scope and high practicability. They include practical hydrogenation of carboxylic and carbonic acid derivatives, hydrogenation and electroreduction of C0 ₂ , various acceptorless

dehydrogenations, asymmetric Michael reaction of 1,3-dicarbonyl compounds with cyclic enones and nitroalkenes, stereoselective catalytic C-N and C-C bond- forming reactions, aerobic oxidative kinetic resolution of racemic secondary alcohols, asymmetric hydration of nitriles and others.

[0006] Given the utility of these catalysts, there is interest in further ligand and catalyst design. SUMMARY

[0007] The present invention is directed to several new classes of ligands, transition metal complexes comprising these ligands, and methods of hydrogenating substrates using these complexes as precatalysts. Some of these ligands show an insensitivity to air, the ability to easily vary structures based on cheap, readily available starting materials (i.e. fine-tuning of ligand conformational, steric and electronic properties) and use simple synthetic procedures and protocols consistent with the concept of green chemistry.

[0008] Some embodiments of the present invention include ligands having a structure of any one of Formula (I), Formula (II), Formula (III), or Formula (IV):

wherein

E is:

Ri and R ₅ are independently at each occurrence optionally substituted Ci_ ₆ alkyl, C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; R5 may also be independently optionally substituted alkoxy or optionally substituted aryloxy;

R ₂ , R3, and R4 are independently at each occurrence H, optionally substituted Ci_ ₆ alkyl, C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; and

m is 1, 2, 3, 4, or 5;

n is 1, 2, 3, 4, or 5;

q is 1, 2, 3, or 4; and

z is 0 or 1, provided that the ligand of Formula (I) is not:

[0009] Other embodiments include those ligands having a structure of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX) or Formula (X):

3 or an achiral isomer, enantiomer, diasteriomer, isomeric mixture, and/or salt thereof,

wherein

Ri, R ₂ , q, and z are as defined for the ligands of Formulae (I) to (IV);

m is independently 1 , 2, 3, 4, or 5;

n is independently 1 , 2, 3, 4, or 5;

z is independently 0 or 1 ;

Rs is H, -(CH ₂ ) _n -S-Ri or -(CH ₂ ) _n -(2-thiophenyl) or -(CH ₂ ) _n -P(0) _z (R ₅ ) ₂ ; and

R ₇ and R ₈ are independently H, optionally substituted Ci_ ₆ alkyl, optionally substituted aryl or heteroaryl, or optionally substituted arylalkyl, or together with the carbons to which they are bound form a 5-7 membered cyclic or heterocyclic ring, provided that only one of R ₇ and Rs is H. Note that in the structures of Formulae (IX) and (X), when z is 0, the carbonyl group is replaced by a methylene group.

[0010] Subset genera and specific examples are recited as separate embodiments within each of these embodiments. In certain of these subsets, the optionally substituted Ci_ ₆ alkyl of R ₂ comprise pendant phosphine or phosphine oxide moieties as described further herein.

[0011] Still other embodiments include those metal coordination complexes comprising any of the ligands described herein coordinated to at least one transition metal. These

coordination complexes, also described herein as precatalysts, include mononuclear and dinuclear metal complexes. Subset general and specific examples are recited as separate embodiments of this class of embodiments.

[0012] Further embodiments of the present invention include the use of the inventive catalysts in and methods of affecting the catalytic hydrogenation of unsaturated organic precursors, including the methods of affecting these transformations. Subset genera of these embodiments include those where the source of hydrogen is dihydrogen, isopropanol, formic acid, or formic acid-triethylamine azeotropic mixture, or a combination thereof, and where the reducible organic substrate comprises at least one unsaturated >C=C< (alkenyl), -C≡C- (alkynyl), >C=0, >C=N- -C≡N, -N=0, or -N=N- (azo) bond. Additional embodiments include the use of the inventive catalysts especially, but not exclusively, the bifunctional catalysts in and methods of affecting the catalyses of dehydrogenation of alcohols and boranes, various dehydrogenative couplings, and catalytic stereoselective and achiral C-N and C-C bond-forming reactions, hydration of nitriles, aerobic oxidative transformation of alcohols into ketones and esters.

[0013] In such methods, the active catalyst either is the coordination complex as- described or is derived in situ from the presence of the coordination complex under the reaction conditions. While the methods do not depend on the correctness or incorrectness of any suggested catalytic model, it is likely the complex affecting the transformation involves a combination of both of as-described and in sz ^' tw-derived complexes. In specific subgenera, the reaction conditions include the use of strong inorganic base, e.g., alkoxides, as a co-catalyst.

[0014] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims. Other aspects of the present invention will be apparent to those skilled in the art in view of the detailed description of the invention as provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings exemplary embodiments of the invention; however, the invention is not limited to the specific methods, compositions, and devices disclosed. In addition, the drawings are not necessarily drawn to scale. In the drawings:

[0016] FIG. 1 and FIG. 2 show structures of several of the inventive ligands.

[0017] FIG. 3 A and FIG. 3B show generic structures of several of the inventive ruthenium catalysts.

[0018] FIG. 4 shows generic structures of several of the inventive iridium catalysts. The various terms are described in the specification.

[0019] FIG. 5 and FIG. 6 show specific structures prepared during the course of this work. An asterisk (*) indicates that the structure has been determined by X-ray crystallography. [0020] FIG. 7 shows selected X-Ray molecular structures for complexes C-2, F-l, D- 1 CH ₂ C1 ₂ , Cu-4, Cu-5 and Cu-8-4MeCN-pentane (50% level of thermal ellipsoids). H-atoms (except NH and OH) are omitted for clarity.

[0021] FIG. 8 shows a potential mechanism for the conversion of iridium chloride catalysts to a proposed iridium dihydride intermediate generated under hydrogenation conditions.

DETAILED DESCRIPTION

[0022] The present invention is directed to several new classes of ligands, catalysts comprising these ligands, and methods of catalyzing a wide range of reactions using these catalysts.

[0023] The present invention may be understood more readily by reference to the following description taken in connection with the accompanying Figures and Examples, all of which form a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, processes, conditions or parameters described or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless specifically otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement. Throughout this specification, claims, and drawings, it is recognized that the descriptions refer to compositions (e.g., ligands and catalysts) and processes of making and using said compositions. That is, where the disclosure describes or claims a feature or embodiment associated with a composition or a method of making or using a

composition, it is appreciated that such a description or claim is intended to extend these features or embodiment to embodiments in each of these contexts (i.e., compositions, methods of making, and methods of using; e.g., features of ligands may be incorporated into the corresponding catalysts, and vice versa).

[0024] Terms

[0025] In the present disclosure the singular forms "a," "an," and "the" include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a material" is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth. [0026] When a value is expressed as an approximation by use of the descriptor "about," it will be understood that the particular value forms another embodiment. In general, use of the term "about" indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word "about." In other cases, the gradations used in a series of values may be used to determine the intended range available to the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0027] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.

[0028] The transitional terms "comprising," "consisting essentially of," and "consisting" are intended to connote their generally in accepted meanings in the patent vernacular; that is, (i) "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method or process steps; (ii) "consisting of excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. Embodiments described in terms of the phrase "comprising" (or its equivalents), also provide, as embodiments, those which are independently described in terms of "consisting of and "consisting essentially of." For those embodiments provided in terms of "consisting essentially of," the basic and novel characteristic(s) of a process is the ability to provide efficient catalysts for the any of the catalytic reactions discussed herein, including reduction of organic substrates and carbon dioxide, oxidation (e.g., acceptorless dehydrogenation of secondary alcohols and aerobic oxidation with oxygen), borylative cyclization, and stereoselective catalytic C-N and C-C bond-forming reactions, catalytic hydration.

[0029] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" is to be interpreted as including the embodiments, "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C." Similarly, for example, where some embodiments of m and n are described in terms of 1 , 2, 3, 4, or 5, it should be appreciated that these also include those embodiments were m and/or n are 1; 2; 3; 4; 5; 1 or 2; 1 or 3; 1 or 4; 1 or 5; 2 or 3; 2 or 4; 2; or 5; 3 or 4; 3 or 5; 4 or 5; 1, 2, or 3; 1, 2, or 4; 1, 2, or 5; 1, 3, or 4; 1, 3, or 5; 1, 4, or 5; 2, 3, or 4; 2, 3, or 5; 2, 4, or 5; 3, 4, or 5; 1, 2, 3, or 4; or 1, 2, 3, or 5.

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are described herein.

[0031] Throughout this specification, words are to be afforded their normal meaning, as would be understood by those skilled in the relevant art. However, so as to avoid

misunderstanding, the meanings of certain terms will be specifically defined or clarified.

[0032] The term "alkyl" as used herein refers to a linear, branched, or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, preferably 1 to about 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. The term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms, and the specific term "cycloalkyl" intends a cyclic alkyl group, typically having 3 to 8, preferably 5 to 7, carbon atoms. The term "substituted alkyl" refers to alkyl groups substituted with one or more substituent groups. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, and/or substituted alkyl and lower alkyl groups, respectively. [0033] The term "alkoxy" as used herein intends an optionally substituted alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as - O-alkyl where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing 1 to 6 carbon atoms.

[0034] The term "aromatic" refers to the ring moieties which satisfy the Hiickel 4n + 2 rule for aromaticity, and includes both aryl (i.e., carbocyclic) and heteroaryl (also called heteroaromatic) structures, including aryl (e.g., phenyl), aralkyl (e.g., benzyl), alkaryl (e.g., tolyl), heteroaryl (e.g., pyridinyl), heteroaralkyl (e.g., pyridinylmethylene), or alk-heteroaryl (e.g., methylpyridinyl) moieties, or oligomeric or polymeric analogs thereof.

[0035] The term "aryl" as used herein, and unless otherwise specified, refers to an optionally substituted aromatic substituent or structure containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Unless otherwise modified, the term "aryl" refers to carbocyclic structures. Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 6 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, tolyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl substituents in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra.

[0036] The term "aryloxy" as used herein refers to an optionally substituted aryl group bound through a single, terminal ether linkage, wherein "aryl" is as defined above. An "aryloxy" group may be represented as -O-aryl where aryl is as defined above.

[0037] The terms "aralkyl" or "arylalkyl" refer to an alkyl group with an optionally substituted aryl substituent, wherein "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain 6 to 24 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, and the like.

[0038] The term "acyl" refers to substituents having the formula -(CO)-alkyl, -(CO)- aryl, or -(CO)-aralkyl, and the term "acyloxy" refers to substituents having the formula -O(CO)- alkyl, -0(CO)-aryl, or -0(CO)-aralkyl, wherein "alkyl," "aryl, and "aralkyl" are as defined above.

[0039] The term "catalyst" is intended to connote a compound, including a transition metal coordination complex, capable of catalyzing a synthetic reaction, as would be readily understood by a person of ordinary skill in the art. The term is used in the present context of coordination complexes for clarity and convenience only, and is not intended to limit the scope of such complexes to this purpose. In this regard, the terms coordination complex and catalyst may be used interchangeably, and the person of ordinary skill would be able to understand as such in the context of the description. As is understood by those skilled in the art, the term "bifunctional M/NH catalyst" refers to a transition metal complex bearing at least one NH functionality. It is not intended to limit, in any way, the number or types of catalytic reactions to which the catalyst may be effectly applied.

[0040] The terms "cyclic" and "ring" refer to alicyclic or aromatic groups that may or may not be substituted and/or heteroatom-containing, and that may be monocyclic, bicyclic, or polycyclic. The term "alicyclic" is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or polycyclic. The term "acyclic" refers to a structure in which the double bond is not contained within a ring structure.

[0041] The terms "halo," "halide," and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.

[0042] As used herein, the terms "substrate" or "organic substrate" are intended to connote both discrete small molecules (sometimes described as "organic compounds") and oligomers and polymers containing the named functional group or unsaturated bond.

[0043] The term "ligand" is intended to connote a compound capable of coordinating to a metal atom or ion, including transition metal, or a compound which is actually coordinated to such a metal, including transition metal, atom or ion. The term is used in the present context for clarity and convenience only, and is not intended to limit the scope of such compounds to this purpose. In this regard, reference to compounds and ligands are used interchangeably, and the person of ordinary skill would be able to understand as such in the context of the description. In addition, where a structure or formula is presented for a ligand or compound, it should also be appreciated that this structure or formula includes any corresponding salt. In the case of amines, this includes amines quaternized, for example, by alkyl or benzyl halides or protic acids.

[0044] By "substituted" as in "substituted alkyl," "substituted aryl," and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, heteroaryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. Examples of such substituents include, without limitation, functional groups such as halo (e.g., F, CI, Br, I), hydroxyl, C ₁ -C24 alkyl (including C3-8 cycloalkyl), C1-C24 alkoxy, C5-C24 aryl, C5-C24 aryloxy, acyl (including C1-C24

alkylcarbonyl (-CO-alkyl) and C6-C24 arylcarbonyl (-CO-aryl)), C2-C24 alkoxycarbonyl ((CO)- O-alkyl), C ₆ -C ₂ 4 aryloxycarbonyl (-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)-NH ₂ ), cyano(-C≡N), formyl (-(CO)-H), nitro, amino ( -NH ₂ ), mono-(Ci-C24 alkyl)-substituted amino, di-( C ₁ -C24 alkyl)-substituted amino, phosphines, and phosphine oxides. Within these substituent structures, the "alkyl," "alkylene," "alkenyl," "alkenylene," "alkynyl," "alkynylene," "alkoxy," "aromatic," "aryl," "aryloxy," "alkaryl," and "aralkyl" moieties may be optionally fluorinated or perfluorinated. Additionally, reference to alcohols, aldehydes, amines, carboxylic acids, ketones, or other similarly reactive functional groups also includes their protected analogs.

[0045] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes embodiments where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. It is to be understood that the various pendant groups (including the 2-thiophenyl groups) are intended to include both substituted and unsubstituted moieties. It is also to be understood that, in certain embodiments, the term

"optionally substituted" applies to the terms alkyl, alkylene, alkenyl, alkenylene,alkynyl, alkynylene, alkoxy, aromatic, aryl, heteraryl, aryloxy, alkaryl, and aralkyl (including their specific exemplars, e.g., phenyl), even if not explicitly stated as such (for example, in provided structure depictions) - i.e., the structures included substituted and unstubstituted embodiments.

[0046] Ligands [0047] Certain specific embodiments of ligands include those having a structure of Formula (I), Formula (II), Formula (III), or Formula (IV):

Ri and R ₅ are independently at each occurrence optionally substituted Ci_ ₆ alkyl, C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; R ₅ may also be independently optionally substituted alkoxy or optionally substituted aryloxy;

R ₂ , R3, and R4 are independently at each occurrence H, optionally substituted Ci_ ₆ alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; and

m is 1, 2, 3, 4, or 5;

n is 1, 2, 3, 4, or 5;

q is 1, 2, 3, or 4; and

z is 0 or 1. See also FIG. 1

[0048] In certain of these embodiments, any one or more (i.e., including any subset collection) of the compounds:

is independently excluded from the scope of Formula(I). In other embodiments, the compounds of Formula (I), where m = n = 1 and Ri is phenyl and E is morpholinyl, piperazinyl, pyrrolidinyl, or dimethylamino are specifically excluded from the scope of the present invention. In still other embodiments, the compounds of Formula (I), where m = n = 1 and Ri is phenyl are excluded from the scope of the present invention. In other separate and independent embodiments of the compounds of Formula (I), when m = 1 or 2, n= 1 or 2, then E is independently not phenyl or not methyl. In still other embodiments of the compounds of Formula (I), when m = 1 or 2, n = 1 or 2, Ri is methyl or phenyl, and E is morpholinyl, piperazinyl, and pyrrolidinyl, or dimethylamino, then R ₂ is not H.

[0049] Even more generally, it should be appreciated that any compound (ligand or coordination complex / catalyst) known at the time of the invention is to be considered a separate exclusion to the more general descriptions provided here. However, where the ligand by itself is excluded as above, the coordination complex / catalyst may still be considered within the scope of the invention. For example, whereas these various described compounds, genera, or subgenera may be excluded from the scope of this invention as ligands or discrete compounds, those catalysts, including those of ruthenium and iridium, which comprise these ligands may still be within the scope of the invention. That is, in certain separate embodiments, the descriptions of catalysts include and exclude the specific genera, subgenera, or complexes comprising these ligand compounds. Both are are considered within the scope of the invention.

[0050] In addition to the descriptions provided elsewhere herein for the definition of optionally substituents, certain other embodiments in the preceding context include those where the optional substituents include amino, alkyl, alkoxy, alkoxycarbonyl, aryl, aryloxy,

carboxylato, C ₃ _6 cycloalkyl, halo, hydroxy, hydroxycarbonyl, thioalkyl, or thiolaryl. In certain specific independent embodiments, the term "optionally substituted Ci_ ₆ alkyl," at least with respect to R ₂ , includes the substitutents:

where independent embodiments provide for any of the various permutations of n, z, and R5 are defined herein. In certain of these embodiments, n is 1, 2, or 3 (preferably 2), z is 0 or 1, and Ri, and R ₅ are phenyl.

[0051] Other inventive ligands include those having a structure of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X):

or an achiral isomer, enantiomer, diasteriomer, isomeric mixture, and/or salt thereof,

wherein

Ri, R ₂ , n, and z are as defined as for the compounds of Formulae (I) to (IV) (note that in the structures of Formulae (IX) and (X), when z is 0, the carbonyl group is replaced by a methylene);

Rs is H, -(CH ₂ )n-S-Ri or -(CH ₂ ) _n -(2-thiophenyl) or -(CH ₂ ) _n -P(0) _z (R ₅ ) ₂ ; and

R ₇ and R ₈ are independently H, optionally substituted Ci_ ₆ alkyl, optionally substituted aryl or heteroaryl, or optionally substituted arylalkyl, or together with the carbons to which they are bound form a 5-7 membered cyclic or 5-7 membered heterocyclic ring, provided that only one of R ₇ and Rg is H. Such heterocyclic rings include those comprising 1 or 2 independent O or N ring atoms. Such exemplary structures include those wherein R ₇ and R ₈ , together with the carbons to which they are attached, form an optionally substituted cyclopentyl, cyclohexyl, [l,4]dioxanyl, or [l,3]dioxolanyl ring. Such embodiments include structures such as:

wherein Rg is -H, -CH ₂ CH ₂ S(phenyl). -CH ₂ CH ₂ P(=0)(phenyl) ₂ , or - CH ₂ CH ₂ P(phenyl) ₂ ; and

where each Ri is independently phenyl, benzyl, methyl, tert-butyl. See also FIG. 2.

[0052] Further independent embodiments include those ligands of Formulae (I) to (X), in which Ri is independently methyl, phenyl, or benzyl.

[0053] Still further independent embodiments include those ligands of Formulae (I) to (X), in which each R ₂ is independently H, benzyl, methyl, naphthyl, phenyl, propyl,

ethylenediphenyl phosphine or ethylenediphenyl phosphine oxide.

[0054] Yet other independent embodiments include those ligands of Formulae (I) to (XII), in which each R ₃ is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert- butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl (- Bn), or phenyl (-Ph), or any subset thereof (e.g., H, methyl, phenyl, or benzyl; or H or methyl).

[0055] The ligands of Formulae (I) to (X) may also independently comprise

embodiments where R ₅ is independently lower alkyl, cycloalkyl, or phenyl.

[0056] To this point, the substituent E has been described in terms of structures where q is 1, 2, 3, or 4, or any combination thereof, but in particular independent embodiments, n is 1 or 2, such that E is oxadolidinyl, morpholinyl, imidazolidinyl, N-methyl-imidazolidinyl, piperazinyl, N-methyl-piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,

dimethylamino, diethylamino, or ethylmethylamino. In other embodiments, E is diarylphosphine or diarylphosphine oxide, dialkylphosphine or dialkylphosphine oxide, alkylarylphosphine or alkylarylphosphine oxide, diarylphosphite or diarylphosphate, dialkylphosphite or

dialkylphosphate, or alkylarylphosphite or alkylarylphosphate.

[0057] Similarly, m and n have been described in terms of 1, 2, 3, 4, or 5, or any subset thereof. In particular independent embodiments of Formulae (I) to (X), m = n = 1, provided that the ligand / compound is not excluded as described herein. In other embodiment, m is 1 and n is 1, 2, 3, 4, or 5, or a subset thereof. Other embodiments of Formulae (I) to (X) provide that n is 1 and m is 1, 2, 3, 4, or 5, or a subset thereof. Similarly, m and n may be independently 2, 3, 4, or 5, or any subset thereof, as applied to any of the compounds of Formulae (I) to (X).

[0058] It should also be appreciated that each of the embodiments described in terms of the ligands of Formulae (I) to (X) may be applied in combination with any other described embodiment(s).

[0059] In some non-limiting examples, the ligands have a structure:

or

[0060] In other non-limiting examples, the ligands have a structure:

where z is 0 or 1. In specific examples of these, R ₂ is H or methyl.

[0061] Some exemplary ligands of Formula (I), in which in which m = n =1 and Ri is benz l and R ₂ is hydrogen include the following:

[0062] Some exemplary ligands of Formula (I), in which in which

22







 [0065] Some exemplary ligands of Formula (I), in which in which m = 1, n = 2, Ri is phenyl and R ₂ is alkyl or aryl include the following:

30

31

33





[0070] A comparable diversity of structures is also available for the other ligands of Formulae (II) to (X).

[0071] Also, so as to help with later descriptions, the ligands of Formulae (I) to (XII) may be described in terms of their heteroatom functionality as NNS-type, P(0)NS-type, PNS- type, SNNS-type, SNNP(0)-type, or SNNP-type ligands, depending on the specific nature of E

[0072] Catalysts

[0073] The present invention is also directed to the coordination complexes or catalysts which comprise at least one of the inventive ligands. Again, the terms coordination complex and catalyst may be used interchangeably and are intended to refer to the organometallic entity. While the complexes are useful as catalysts, the use of the term catalyst should not be interpreted to limit the scope of the complexes to this purpose

[0074] Some of these catalysts comprise catalysts having at least one ligand of Formulae (I) to (X), including NNS-type, P(0)NS-type, PNS-type, SNNS-type, SNNP(0)-type, or SNNP- type ligands, or any described permutations thereof, coordinated to at least one transition metal. As exemplified in the Examples, such catalysts may be formed by reacting a suitable transition metal precursor with at least one of the ligands described herein. In many cases, this involves the reaction of the corresponding metal chloride or metal olefin complex with the appropriate ligand. While the ligands have been described in terms of certain exclusions, for example, excluding:

among other specific and generic ligand embodiments, the catalysts are not necessarily so limited, and in separate embodiments, the catalysts may be free of any individual or combination of excluded ligands or include and or all such ligands or ligand embodiments described herein.

[0075] As used herein, the term "transition metal" includes any metal of Group 4 to Group 12, including the lanthanides and actinides, preferably one of the Group 6 to Group 11 transition metals. Such transition metals include, but are not limited to Ti, V, Zr, Hf, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, La, Ni, Pd, Pt, Cu, Ag, Au, Zn, and Sm, preferably Cr, Co, Cu, Fe, Mn, Mo, Ni, Os, Pd, Rh, Sm, or W, or any subset combination thereof. In some

embodiments, the catalysts comprise Fe, Ru, Os, Co, Rh, or Ir, or any subset combination thereof. See also FIG. 6. In other specific embodiments, the catalysts comprise ruthenium or iridium.

[0076] Some of the catalysts may be described more specifically in terms of their stoichiometries. For example, in some independent embodiments, the ratio of the ligand to transition metal is usually 1 to 1. Further, the catalysts may contain one, two, or more transition metals per molecular entity. The ligands may bridge multiple transition metal centers, or may be monodentate, bidentate, tridentate, or tetradentate with respect to any individual transition metal center.

[0077] Depending on the nature of the transition metal and ligand combination, other ligands, including formally anionic ligands, neutral ligands, or cationic ligands, may be coordinated to the transition metal. Exemplary anionic ligands include optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy (e.g., methoxy or benzyloxy), optionally substituted aryloxy (e.g., phenoxy), optionally fluorinated carboxylato (e.g., mono-, di-, or trifluoroacetic acid), halo (including fluoro, chloro, bromo, iodo), hydrido, hydroxy, NO, OTf (triflate), OTs (tosylate), phosphate, or BH ₄ . In some embodiments, at least one of the formally anionic ligands is chloro. [0078] Exemplary neutral ligands include C, N, O, P, or S-bonded ligands, such as are known in the art for such transition metal complexes. Such ligands include alkyl or aryl nitriles, alkyl, aryl, or unsubstituted primary, secondary, or tertiary amines, carbonyl, alkyl or aryl ethers (including cyclic ethers, such as tetrahydrofuran), olefins, phosphines, phosphine oxides, phosphites, or alkyl or aryl sulfoxide or other solvent molecules (including lower alcohols and water). Phosphines, phosphine oxides, and phosphites can comprise optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl moieties, again as are known in the art.

[0079] In certain specific embodiments, the catalysts may comprise ruthenium having an empirical formula Ru(NNS)XiX ₂ L, Ru[P(0)NS]XiX ₂ L, Ru(PNS)XiX ₂ L, Ru(SNNS)XiX ₂ L, Ru[SNNP(0)]XiX ₂ L, or Ru(SNNP)XiX ₂ L wherein

NNS, P(0)NS, PNS, SNNS, SNNP(O), or SNNP is a NNS-type, P(0)NS-type, PNS- type, SNNS-type, SNNP(0)-type, or SNNP-type, respectively;

Xi and X ₂ are independently formally anionic ligands; and

L is absent or a neutral ligand. L may be absent, for example, when the coordination sphere of the Ru is satisfied without the need for another neutral ligand.

[0080] In some embodiments, the catalysts comprise ruthenium having an empirical formula Ru(NNS)XiX ₂ L, wherein NNS, X _ls X ₂ , and L are as described herein. The catalyst may be independently mononuclear or dinuclear with respect to the ruthenium.

[0081] Certain exemplary, non-limiting embodiments provide that the structures of the inventive ruthenium complexes may be represented as:

or an isomer thereof, wherein R _{l s} R ₂ , R3, Xi, X ₂ , m, n, z, and E are defined in terms of any of the definitions for these terms provided herein. See also FIG. 3A and 5.

[0082] Additional specific embodiments include those of Structures (A) to (H), wherein:

Xi and X ₂ are independently halo (especially CI), H, OTf, BH ₄ ,

m and n are independently 1 , 2, 3, 4, or 5, or a subset thereof;

z is independently 0 or 1 ;

L is independently -S(=0)(CH ₃ ) ₂ , -CO, -PPh ₃ , -PCy ₃ , -PMe ₃ , -P ^f Pr ₃ , -P'Bu ₃ , or

-PPh ₃ and

Ri is alkyl, aryl, or arylalkyl ( e.g., methyl, phenyl, and benzyl);

R ₂ is H, alkyl, aryl, or arylalkyl (e.g., methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert-butyl, benzyl, or phenyl); and

R ₃ is alkyl, aryl, or arylalkyl (for methyl (-CH ₃ ), cyclohexyl (-Cy), benzyl (-Bn, -CH ₂ Ph), phenyl (-Ph) or napthyl).

[0083] Structures (A) where:

(i) m = n = 1 , Xi = Xi = CI, L is PPh ₃ , and Ri is separately methyl, benzyl, or phenyl;

(ii) m = n = 1 , Xi = Xi = CI, Ri is phenyl, and L is CH ₃ S(0)CH ₃ ; and

(iii) m = 1 , n = 2, Xi = Xi = CI, Ri is benzyl, and L is PPh ₃ ;

Structures (B) and (C) where (i) Ri is phenyl, R ₂ is H, R ₃ is methyl, and L is PPh ₃ ; Structure (D) where m = n = 1, Ri is methyl, R ₂ is H, R ₅ is phenyl, and Xi is CI; and

Structure (F) where m = n = 1, Ri is phenyl, and R ₂ is H, have all been characterized crystallographically in these conformations.

[0084] Further exemplary, non-limiting embodiments include those where the structures of the inventive ruthenium complexes may be represented as:

or an isomer thereof, wherein

the variables presented, including R ₂ , R ₃ , m, n, and E, are defined in terms of any of the definitions for these terms provided herein. See also FIGs. 3B and 5.

[0085] Additional specific embodiments include those compounds of Structures (J), (K), or (L) wherein:

m and n are independently 1, 2, 3, 4, or 5 or a subset thereof;

Ri is alkyl, aryl, or arylalkyl( e.g., methyl, phenyl, and benzyl); P 2 is H, alkyl, aryl, or arylalkyl (e.g., methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert-butyl, benzyl, or phenyl);

L is independently -S(=0)(CH ₃ ) ₂ , CO, or -PPh ₃ , -PCy ₃ , -PMe ₃ , -P ^f Pr ₃ , -P'Bus, or-PPh ₃ ; E is

each R ₃ is independently methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert- butyl, benzyl (-Bn), and phenyl (-Ph), and

q is 1, 2, 3, or 4. Exemplary related structures are shown in FIGs. 3A, 3B, and 5.

[0086] Structure (J), where m = 2, n = 1, L = PPh ₃ , and E is morpholinyl, and Structure (K) where m = n = 1 and E is morpholinyl have been characterized crystallographically in these conformations, though other conformers, isomers, or toutomers may exist in solution.

[0087] In other embodiments, the catalysts may comprise iridium having an empirical formula Ir(NNS)XiL, Ir[P(0)NS]XiL, Ir(PNS)XiL, Ir(SNNS)XiL, Ir[SNNP(0)]XiL, or

Ir(S NP)XiL wherein

NNS, P(0)NS, PNS, SNNS, SNNP(O), or SNNP is a NNS-type, P(0)NS-type, PNS- type, SNNS-type, SNNP(0)-type, or SNNP-type, respectively;

Xi is a formally anionic ligand; and

L is a neutral ligand.

[0088] In preferred embodiments, the catalysts comprise iridium having an empirical formula Ir(NNS)X ₁ L, wherein NNS, Xi, X ₂ , and L are as described herein.

[0089] In this regard, certain other exemplary, non-limiting embodiments provide that the structures of the inventive iridium com lexes may be represented as:

or an isomer thereof, wherein R ₂ , Xi, m, n, and E are defined in terms of any of the definitions for these terms provided herein. Such structures include, for example:

Additional related structures are shown in FIGs. 4 and 5. In certain aspects of these N-structures, ortho-metallated complexes may be seen as tautomer of the un-metallated complex, and isomer includes geometric isomers, for example, having ligands positioned differently than shown.

[0090] Similarly, in some organometallic complexes containing PN(H)P-type ligands, the saturated ethylene bridges between the N and P moieties are known to reversibly hydrogenate / dehydrogenate, converting these bridges to unsaturated ethenylene linkages. See, e.g., Κ¾β et ah, Angew. Chem. Int. Ed. 2009, 48, 905. Such structures having unsaturated ethenylene

linkages would be considered tautomers of the presently inventive complexes and within the scope of the present invention as such.

[0091] Additional specific embodiments include those wherein m and n are

independently 1, 2, 3, 4, or 5, or a subset thereof;

Xi is halo (e.g., chloro), optionally fluorinated carboxylato (including trifluoroacetato), H, OTf, or BH ₄ ,;

P 2 is H, alkyl, arylalkyl, or aryl;

E is

(each of these representing independent embodiments)

each P 3 is independently methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert- butyl, benzyl (-Bn), or phenyl (-Ph); and

q is 1, 2, 3, or 4.

[0092] Structure (M), where m = n = 1 and E is morpholinyl, and Structure (N) where (i) m = 2, n = 1 , P 2 is H, and E is morpholinyl and (ii) m = n = 2, E is morpholinyl, and R ₂ is

separately H and methyl, have all been characterized crystallographically in these conformations. [0093] In some iridium complexes, as shown above, the nature of the species described by these empirical formulae comprise ortho-metallated ligands. While such complexes are chemically distinct from their non-ortho-metallated conformers, they may also be described either as isomers or tautomers of one another.

[0094] In the case of at least these ruthenium and iridium complexes, other embodiments have been prepared where L is-S(=0)(CH ₃ ) ₂ , CO, nitrile, or -PPh ₃ , -PCy ₃ , -PMe ₃ , -P ^f Pr _3, - or -PPh ₃ . In the case of iridium complexes, some embodiments include those where L is an olefin or a cycloolefm, for example cyclooctene.

[0095] In addition to the ortho-metallation described above, in some embodiments, the transition metal coordination complex may be capable of oxidatively adding H ₂ , dihalogen (e.g., Cl ₂ , Br ₂ , 1 ₂ ), carboxylate acid (e.g., acetic acid, trifluoroacetic acid, or benzoic acid), hydrogen halide (e.g., HC1, HBr, or HI), alkyl or benzyl halide (e.g., Mel), and dioxygen, as such reactions are known in the art, and the resulting oxidative adducts are considered within the scope of the present invention.

[0096] All of the catalysts described elsewhere herein (including in the Examples), including isomers or tautomers, or N-alkylated, N-arylated, and N-aralkylated derivatives thereof, may be considered within the scope of the present invention.

Catalytic Reactions

[0097] The present invention is also directed to the use of these coordination complexes or catalysts for the hydrogenation of certain substrates, and the methods of affecting these transformations. These hydrogenations may use dihydrogen or formic acid as the source of the hydrogen in these transformations, and the catalyst may be present in the corresponding reaction mixture either as delivered to the reaction or as derived in situ from the presence of catalyst complex under the reaction conditions.

[0098] In certain embodiments, the methods comprise reacting an organic substrate having an unsaturated bond with a source of hydrogen (e.g., dihydrogen, a secondary alcohol, formic acid, or a combination thereof) in the presence of one of the inventive catalysts, under reaction conditions sufficient to hydrogenate the unsaturated bond. The unsaturated bond of the organic substrate may independently be at least one of an >C=C< (alkenyl), -C≡C- (alkynyl), >C=0, >C=N-, -C≡N, -N=0, or -N=N- (azo) bond. In such cases, the organic substrate having the unsaturated C=C, C=0, or C=N bond comprises an aldehyde, ketone, an imine, an imide, a carboxylic acid, an acid anhydride, an ester, an amide (carboxamide), a carbonic anhydride ester (carbonate), a carbamic acid ester (carbamate), or a urea functional group. Organic carbonyl or imine double bonds are particularly attractive substrates for these catalysts. The unsaturated bonds may be functionalized or non-functionalized, conjugated or non-conjugated. Other bifunctional catalysts have been shown to exhibit exceptionally high C=0 / C=C

chemoselectivity, and similar selectivity can reasonably be expected with the inventive catalysts described herein.

[0099] In certain other embodiments, and especially but not exclusively those in which the catalysts are bifunctional (i.e., the ones bearing ligand NH functionalities), the catalysts independently catalyze the hydrogenation of ketones and imines, and in the case of those catalysts containing chiral ligands may provide for asymmetric ketone hydrogenation and stereoselective catalytic C-N and C-C bond-forming reactions (e.g, aziridination of alkenes). Other catalysts provide for the asymmetric transfer hydrogenation of ketones and imines, asymmetric hydrogenation of polar functionalities, asymmetric Michael reaction of 1,3- dicarbonyl compounds with cyclic enones and nitroalkenes, aerobic oxidative kinetic resolution of racemic secondary alcohols and asymmetric hydration of nitriles. Such other catalysts may also be useful for C0 ₂ , carbonates, ester hydrogenation, and various acceptorless

dehydrogenations. Under certain well-understood conditions, these catalysts may act as precatalysts in C0 ₂ hydrogenation and electroreduction, ester hydrogenation, ketone transfer hydrogenations, the so lvo lysis of ammonia borane, and the amination of aliphatic alcohols.

[0100] In certain other embodiments, the methods comprise reacting carbon dioxide, either as carbon dioxide or as a hydration or alcoholic product thereof (e.g., a carbonate) with a source of hydrogen (typically dihydrogen) in the presence of one of the inventive catalysts, under reaction conditions sufficient to hydrogenate the unsaturated bond.

[0101] These reactions may be conveniently conducted in polar or non-polar solvents in the presence of base co-catalysts. Solvents which have been successfully employed include aromatic hydrocarbons (aryl or heteroaryl solvents), alcohols, nitriles, ethers, or even water (see Examples for some specific exemplary, non-limiting examples). The solvents are chosen so as to provide a system wherein at least a portion, and preferably all, of the catalyst, the co-catalyst, the source of hydrogen, and the substrate dissolve to form a solution capable of affecting the desired transformation. The reactions may be conducted in such solvents at even mild temperatures and moderate pressures. Exemplary operable temperature ranges including those ranges from about 10°C to about 15°C, from about 15°C to about 20°C, from about 20°C to about 25°C, from about 25°C to about 30°C, from about 30°C to about 35°C, from about 35°C to about 40°C, from about 40°C to about 45°C, from about 45°C to about 50°C, from about 50°C to about 55°C, from about 55°C to about 60°C, from about 60°C to about 65°C, from about 65°C to about 70°C, from about 70°C to about 75°C, from about 75°C to about 80°C, from about 80°C to about 85°C, from about 85°C to about 90°C, from about 90°C to about 95°C, from about 95°C to about 100°C, from about 100°C to about 120°C, from about 120°C to about 140°C, from about 140°C to about 160°C, from about 160°C to about 180°C, from about 180°C to about 200°C, or any combination of these ranges, for example, from about 20°C to about 100°C, from about 25°C to about 60°C, or from about 35°C to about 50°C. Exemplary pressure ranges include those ranges from about 1 bar to about 2 bar, from about 2 bar to about 3 bar, from about 3 bar to about 4 bar, from about 4 bar to about 5 bar, from about 5 bar to about 10 bar, from about 10 bar to about 15 bar, from about 15 bar to about 20 bar, from about 20 bar to about 25 bar, from about 25 bar to about 30 bar, from about 30 bar to about 40 bar, from about 40 bar to about 50 bar, or any combination of these ranges, for example, from about 2 bar to about 50 bar, or from about 5 bar to about 25 bar, where "bar" refers to absolute pressure. In the case of hydrogen, these conditions provide sufficient dissolution of hydrogen in most solvents to provide a reaction mixture having convenient turnover rates.

[0102] A basic co-catalyst appears to be useful in imparting catalytic activity, especially with the bifunctional complexes. Good success has been achieved using alkoxide bases, for example sodium methoxide, though it is envisioned that other alkali metal or alkaline earth metal alkoxides (e.g., including specifically isopropoxides or tert-butoxides) will work as well.

Without intending to be bound by the correctness or incorrectness of any particular theory, it may be that the alkoxide activates the transition metal catalyst by displacing other anionic ligands. (see, e.g., FIG. 8).

[0103] The catalysts appear to be usefully active, especially those based on ruthenium and iridium, and good success has been achieved under these conditions where the substrate to catalyst ratio is in a range of from about 1000:1 to about 50,000: 1, though the invention is not necessarily limited to these conditions. [0104] The following listing of embodiments is intended to complement, rather than displace or supersede, the previous descriptions.

[0105] Embodiment 1. A ligand having a structure of Formula (I), Formula (II), Formula (III), or Formula (IV):

Ri and R ₅ are independently at each occurrence optionally substituted Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; R5 may also be independently optionally substituted alkoxy or optionally substituted aryloxy;

R ₂ , R ₃ , and R4 are independently at each occurrence H, optionally substituted Ci_ ₆ alkyl, C ₃ _6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl; and

m is 1 , 2, 3, 4, or 5;

n is 1 , 2, 3, 4, or 5;

q is 1 , 2, 3, or 4; and

z is independently 0 or 1. In certain aspects of this Embodiment, R ₂ is not H.

In certain aspects of this Embodiment, the one or more of the following compounds may be individually or collectively, in any subset permutation, excluded from the genus of Formula (I):

Other aspects of this Embodiment exclude the independent compounds of Formula (I) where m = n = 1 and Ri is phenyl and E is morpholinyl, piperazinyl, pyrrolidinyl, or dimethylamino.

In still other embodiments, the compounds of Formula (I), where m is independently 1 or 2, n is independently 1 or 2, and Ri is independently phenyl or methyl are excluded from the scope of the present invention. In other separate and independent embodiments of the compounds of Formula (I), when m = 1 or 2, n= 1 or 2, then E is independently not phenyl or not methyl. In still other independent embodiments of the compounds of Formula (I), when m is independently 1 or 2, n is independently 1 or 2, Ri is independently methyl or phenyl, and E is independently morpholinyl, piperazinyl, and pyrrolidinyl, or dimethylamino in the compounds of Formula (I), then R ₂ is not H. Still other aspects of this Embodiment include the salts of these compounds. [0106] Embodiment 2. A ligand having a structure of Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X):

or an achiral isomer, enantiomer, diasteriomer, isomeric mixture, and/or salt thereof, wherein

Ri, R ₂ , R ₅ , n, and z are as defined in claim 1;

Rs is H, -(CH ₂ ) _n -S-Ri or -(CH ₂ ) _n -(2-thiophenyl) or -(CH ₂ ) _n -P(0) _z (R ₅ ) ₂ ; and

R ₇ and R ₈ are independently H, optionally substituted Ci_ ₆ alkyl, optionally substituted aryl or heteroaryl, or optionally substituted arylalkyl, or together with the carbons to which they are bound form a 5-7 membered cyclic or heterocyclic ring, provided that only one of R ₇ and Rs is H,

[0107] Embodiment 3. The ligand of Embodiment 2, wherein R ₇ and Rs, together with the carbons to which they are attached, form an optionally substituted cyclopentyl, cyclohexyl, [l,4]dioxanyl, or [l,3]dioxolanyl ring.

[0108] Embodiment 4. The ligand of any one of Embodiments 1 to 3, wherein Ri is methyl, phenyl, or benzyl.

[0109] Embodiment 5. The ligand of any one of Embodiments 1 to 4, wherein R ₂ is H, methyl, phenyl, or benzyl.

[0110] Embodiment 6. The ligand of any one of Embodiments 1 to 5, wherein R ₂ is H.

[0111] Embodiment 7. The ligand of any one of Embodiments 1 to 5, wherein R ₂ is not H. In certain aspects of this Embodiment, R ₂ is methyl.

[0112] Embodiment 8. The ligand of any one of Embodiments 1 to 7, wherein R ₃ is independently methyl, ethyl, propyl, isopropyl, 1 -butyl, 2-butyl, isobutyl, tert-butyl, benzyl (- Bn), or phenyl (-Ph).

[0113] Embodiment 9. The ligand of any one of Embodiments 1 to 8, where R ₅ is optionally substituted phenyl. In certain aspects of this Embodiment, R ₅ is unsubstituted phenyl.

[0114] Embodiment 10. The ligand of any one of Embodiments 1 to 9, wherein E is oxadolidinyl, morpholinyl, imidazolidinyl, N-methyl-imidazolidinyl, piperazinyl, N-methyl- piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, dimethylamino, diethylamino, ethylmethylamino, diarylphosphme or diarylphosphme oxide, dialkylphosphine or dialkylphosphine oxide, alkylarylphosphine or alkylarylphosphine oxide, diarylphosphite or diarylphosphate, dialkylphosphite or dialkylphosphate, or alkylarylphosphite or alkylarylphosphate.

[0115] Embodiment 11. The ligand of any one of Embodiments 1 to 10, wherein m and n are 1.

[0116] Embodiment 12. The ligand of Embodiment 11, wherein Ri is methyl or benzyl.

[0117] Embodiment 13. The ligand of any one of Embodiments 1 to 10 or 12, wherein m is 2, 3, 4, or 5 and n is 1. [0118] Embodiment 14. The ligand of any one of Embodiments 1 to 10, wherein m and n are independently 2, 3, 4, or 5.

[0119] Embodiment 15. The ligand of Embodiment 1 or any one of Embodiments 4 to 10, as applied to claim 1, having a structure of Formula (IV).

[0120] Embodiment 16. The ligand of Embodiment 1 or 15, or any one of Embodiments 4 to 10, as applied to claim 1, having a structure of Formula (IV), wherein n is 2.

[0121] Embodiment 17. The ligand of Embodiment 1 having a structure of:

or the ligand of Embodiment 2 having a structure of:

where z is 0 or 1, especially where R ₂ is independently H or methyl.

[0122] Embodiment 18. A coordination complex comprising a ligand coordinated to at least one transition metal, wherein the ligand is at least one compound of Formulae (I) to (IV) of Embodiment 1 or any one of Embodiments 4 to 17, as applied to Embodiment 1.

[0123] Embodiment 19. A coordination complex comprising a ligand coordinated to at least one transition metal, wherein the ligand is at least one compound of Formulae (V) to (X) of Embodiment 2, or any one of Embodiments 3 to 17, as applied to Embodiment 2.

[0124] Embodiment 20. The coordination complex of Embodiment 18 or 19, wherein the transition metal comprises at least one of the Group 4 to Group 12 transition metals, preferably one of the Group 6 to Group 11 transition metals]

[0125] Embodiment 21. The coordination complex of Embodiment 18 or 19, wherein the transition metal comprises at least one of the Ti, V, Zr, Hf, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, La, Ni, Pd, Pt, Cu, Ag, Au, or Zn, preferably Cr, Co, Cu, Fe, Mn, Mo, Ni, Os, Pd, Rh, Sm, or W.

[0126] Embodiment 22. The coordination complex of Embodiment 18 or 19, wherein the transition metal is ruthenium or iridium.

[0127] Embodiment 23. The coordination complex of Embodiment 22, wherein the transition metal is ruthenium, the complex having an empirical formula Ru(NNS)XiX ₂ L, Ru[P(0)NS]XiX ₂ L, Ru(PNS)XiX ₂ L, Ru(SNNS)XiX ₂ L, Ru[SNNP(0)]XiX ₂ L, or

Ru(SNNP)XiX ₂ L wherein NNS, P(0)NS, PNS, SNNS, SNNP(O), or SNNP is a NNS-type, P(0)NS-type, PNS-type, SNNS-type, SNNP(0)-type, or SNNP-type, respectively;

Xi and X ₂ are independently formally anionic ligands; and L is absent or a neutral ligand. In specific aspects of this Embodiment, the complex has an empirical formula of Ru(NNS)XiX ₂ L.

[0128] Embodiment 24. The coordination complex of Embodiment 22, wherein the transition metal is iridium, the complex having an empirical formula Ir(NNS)X ₁ L,

Ir[P(0)NS]XiL, Ir(PNS)XiL, Ir(S NS)XiL, Ir[SNNP(0)]XiL, or Ir(SNNP)XiL wherein NNS, P(0)NS, PNS, SNNS, SNNP(O), or SNNP is a NNS-type, P(0)NS-type, PNS-type, SNNS-type, SNNP(0)-type, or SNNP-type, respectively;

Xi is a formally anionic ligand; and

L is a neutral ligand. In specific aspects of this Embodiment, the complex has an empirical formula of Ir(NNS)XiL.

[0129] Embodiment 25. The coordination complex of Embodiment 23 or 24, wherein Xi and X ₂ are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally fluorinated carboxylato, halo

(including fluoro, chloro, bromo, iodo), hydrido, hydroxy, NO, OTf (triflate), OTs (tosylate), phosphate, or BH ₄ . In certain aspects of this embodiment, Xi and X ₂ are independently alkoxy, fluorinated carboxylato, halo, hydrido, NO, OTf (triflate), OTs (tosylate) or BH ₄ .

[0130] Embodiment 26. The coordination complex of any one of Embodiments 23 to 25, wherein at least one of Xi and X ₂ is chloro.

[0131] Embodiment 27. The coordination complex of any one of Embodiments 23 to 26, wherein L is absent or a[n alkyl or aryl] nitrile, an [alkyl or aryl] amine, carbonyl, an [alkyl or aryl] ether, a[n alkyl or aryl] phosphine, a[n alkyl or aryl] phosphine oxide, a[n alkyl or aryl] phosphite, a[n alkyl or aryl] phosphate or a[n alkyl or aryl] sulfoxide.

[0132] Embodiment 28. The coordination complex of any one of Embodiments 23 to 27, wherein L is -S(=0)(CH ₃ ) ₂ , CO, or -PPh ₃ , -PCy ₃ , -PMe ₃ , -P'Pr ₃ , -P'Bu^ or -PPh ₃ .

[0133] Embodiment 29. The coordination complex of Embodiment 22 or any one of

Embodiments 25 to 28 as applied to claim 18, wherein the coordination complex is a dinuclear complex of ruthenium.

[0134] Embodiment 30. The coordination complex of any one of Embodiments 24 to 26, wherein L is an olefin. [0135] Embodiment 31. The coordination complex of Embodiment 30, wherein L is cyclooctene.

[0136] Embodiment 32. An oxidative addition product of the coordination complex of any one of Embodiments 23 to 29.

[0137] Embodiment 33. The oxidative addition product of Embodiment 32, derived from the addition of H ₂ , dihalogen, hydrogen carboxylate, hydrogen halide, alkyl halide to a corresponding precursor coordination complex. In certain aspects of this Embodiment, the oxidative addition product is derived from the addition of HCl, HBr, HI, Cl ₂ , Br ₂ , 1 ₂ , Mel, acetic acid, benzoic acid, and trifluoroacetic acid.

[0138] Embodiment 34. The coordination complex of Embodiment 18 or 19,

characterized as having a structure of any one of the compounds of FIG. 3 A, FIG. 3B, or FIGs. 4-8, or an isomer or tautomer thereof.

[0139] Embodiment 35. A method comprising reacting an organic substrate having at least one unsaturated >C=C< (alkenyl), -C≡C- (alkynyl), >C=0, >C=N- -C≡N, -N=0, or - N=N- (azo) bond with dihydrogen in the presence of a catalyst under reaction conditions sufficient to reduce the unsaturated bond by the addition of dihydrogen across the unsaturated bond, the catalyst being derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

[0140] Embodiment 36. A method comprising reacting an organic substrate having at least one unsaturated >C=C< (alkenyl), -C≡C- (alkynyl), >C=0, >C=N- -C≡N, -N=0, or - N=N- (azo) bond with formic acid in the presence of a catalyst under reaction conditions sufficient to reduce the unsaturated bond by the addition of dihydrogen across the unsaturated bond, the catalyst being comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

[0141] Embodiment 37. The method of Embodiment 35 or 36, wherein the unsaturated bond is a carbonyl or imine double bond.

[0142] Embodiment 38. The method of any one of Embodiments 35 to 37, wherein the organic substrate having the unsaturated C=C, C=0, or C=N bond comprises a ketone, an imine, an imide, a carboxylic acid, an acid anhydride, an ester, an amide (carboxamide), a carbonic anhydride ester (carbonate), a carbamic acid ester (carbamate), or a urea functional group.

[0143] Embodiment 39. A method comprising reacting carbon dioxide substrate with dihydrogen in the presence of a catalyst, the catalyst comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34, under reaction conditions sufficient to reduce the carbon dioxide by the addition of dihydrogen thereto.

[0144] Embodiment 40. The method of any one of Embodiments 35 to 39, wherein the conditions sufficient to reduce the carbon dioxide or the unsaturated bond comprise reacting the substrate, the catalyst, and the dihydrogen in the presence of a solvent and a strong base.

[0145] Embodiment 41. The method of Embodiment 40, wherein the strong base is an alkali metal or alkaline earth metal alkoxide, preferably a methoxide, isopropoxide, or tert- butoxide.

[0146] Embodiment 42. A method comprising reacting a primary or secondary alcohol (including but not limited to methanol, ethanol, propanol, or isopropanol) in the presence of a catalyst under reaction conditions sufficient to dehydrogenate the primary or secondary alcohol, the catalyst comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

[0147] Embodiment 43. A method comprising reacting a primary or secondary alcohol (including but not limited to methanol, ethanol, propanol, or isopropanol) in the presence of a catalyst under reaction conditions sufficient to dehydrogenate the primary or secondary alcohol, the catalyst comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

[0148] Embodiment 44. A method comprising reacting an alkene substrate and appropriate reactant (as is known in the art), in the presence of a catalyst, under reaction conditions sufficient to form a cycloalkyl (e.g., cyclopropyl) or aziridine moiety, the catalyst comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

[0149] Embodiment 45. A method comprising reacting a nitrile, a borane, or an aliphatic alcohol, in the presence of a catalyst, under reaction conditions sufficient to hydrate the nitrile, solvate the borane, or aminate the alcohol, respectively, the catalyst comprising a coordination complex of any one of Embodiments 18 to 34 or derived in situ from the presence of

coordination complex of any one of Embodiments 18 to 34 under the reaction conditions.

EXAMPLES

[0150] The following Examples are provided to illustrate some of the concepts described within this disclosure. While each Example is considered to provide specific individual embodiments of composition, methods of preparation and use, none of the Examples should be considered to limit the more general embodiments described herein.

[0151] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless indicated otherwise, temperature is in degrees Celsius, pressure is at or near atmospheric.

[0152] Example 1. Materials and Methods.

[0153] Phosphorus tribromide (99%, CAS Number 7789-60-8), 2-(phenylthio)ethanol (99%, CAS Number 699-12-7), 2-(methylthio)ethanol (99%, CAS Number 5271-38-5), ethylene sulfide (98%, CAS Number 420-12-2), trimethylene sulfide (>96.0%, CAS Number 287-27-4), 2-(4-morpholinyl)ethanamine (99%, CAS Number 2038-03-1), 3-morpholinopropylamine (CAS Number 123-00-2), l-(2-aminoethyl)pyrrolidine (98%, CAS Number 7154-73-6), l-(2- aminoethyl)piperazine (99%, CAS Number 140-31-8), 2-chloroethyl methyl sulfide (97%, CAS Number 542-81-4), 2-thiophenecarbaldehyde (98%, CAS Number 98-03-3), (lR,2R)-(-)-\,2- diaminocyclohexane ((R,R)-OACH, 98%, CAS Number 20439-47-8), diphenylvinylphosphine (95%, CAS Number 2155-96-6), H ₂ 0 ₂ (30 wt. % in H ₂ 0, CAS Number 7722-84-1), (2- methylthio)ethylamine (97%, CAS Number 18542-42-2) were purchased from Sigma Aldrich and used as received or preliminary distilled for selected liquids (see experimental procedures). Benzyl bromide (99%>, CAS Number 100-39-0) was purchased from Alfa Aesar, N,N- dimethylethylenediamine (>97.0%, CAS Number 108-00-9) was purchased from TCI. Anhydrous potassium carbonate (>99.0%) was purchased from Fischer Scientific, sodium methoxide (95%, powder, CAS Number 124-41-4) from Sigma Aldrich.

(Phenylsulfanyl)acetaldehyde (CAS Number 66303-55-7) was synthesized as described in J. Org. Chem. 1995, 60, 1276. All solvents for organic synthesis were purchased from Sigma Aldrich and used as received.

[0154] All syntheses of organometallic complexes were performed in an MBraun Labmaster 130 glovebox under argon. Dichloromethane (anhydrous, >99.8%, Sigma Aldrich), toluene (anhydrous, 99.8%, Sigma-Aldrich), THF (anhydrous, >99.9%%, Sigma Aldrich), diethyl ether (anhydrous, >99.7%, Sigma Aldrich), pentane (anhydrous, >99%>, Sigma Aldrich), methanol (anhydrous, 99.8%>, Sigma Aldrich), acetonitrile (anhydrous, 99.8%>, Sigma Aldrich), absolute ethanol (>99.5%, Sigma Aldrich), [RuCl ₂ (PPh ₃ ) ₃ ] (97%, CAS Number 15529-49-4, Sigma Aldrich), [RuCl ₂ (r| ⁴ -COD)]„ (97%, CAS Number 50982-12-2, STREM),

[RuCl ₂ (DMSO) ₄ ] (96%, CAS Number 89395-66-4, Sigma Aldrich), [IrCl(r| ² -COE) ₂ ] ₂ (97%, CAS Number 12246-51-4, Sigma Aldrich), MnCl ₂ (>99%, Sigma Aldrich), FeCl ₂ (98%, Sigma Aldrich), CoCl ₂ (97%, Acros Organics), NiCl ₂ (98%, Acros Organics), CuCl ₂ (>99.995%, Sigma Aldrich), Ru-MACHO (739103 Aldrich), Gusev's Ru-SNS (97%, 746339 Aldrich), Milstein's Ru-PNN (735809 Aldrich), ^i? Ts-DENEB (T3078, TCI), (i?)-RUCY-XylBINAP (R0139, TCI), Abdur-Rashid's Ir-PNP (min 98%, 77-0500 Strem) were used as received.

[0155] Elemental Analyses were performed by Midwest Microlab, LLC (Indianapolis, IN 46250) under air or under inert atmosphere of nitrogen or argon. All NMR experiments were carried out using a Bruker AV400 MHz spectrometer. 1H and ^C ^FI} NMR spectra were calibrated by using the residual deuterated solvent signal relative to TMS in ppm (δ). ¹⁹ F NMR spectra were measured without lock but properly shimmed in methanol and calibrated relative to 2,2,2-trifluoroethanol (product C), with δ set at -77.0 ppm. Magnetic susceptibility

measurements (Gouy balance, Sherwood Scientific, r.t.) were performed with diamagnetic correction. X-Ray Data for C-2 were collected on a Bruker D8 Quest diffractometer, with CMOS detector in shutterless mode. The crystal was cooled to 100 K employing an Oxford Cryostream liquid nitrogen cryostat. Data for F-1, D-1, Cu-4, Cu-5 and Cu-8 were collected on a Bruker D8 diffractometer, with an APEX II CCD detector. The crystals were cooled to 140 K using a Bruker Kryoflex liquid nitrogen cryostat. Both instruments employed graphite monochromatized ΜοΚα (λ= 0.71073 A) radiation. For Cu-8, disordered acetonitrile and pentane solvent molecules were treated with Platon/Squeeze (4 acetonitrile and 1 pentane solvent per copper dimer). For D-l a disordered dichloromethane molecule was refined in two partial occupancy positions. The structures F-1, Cu-4, Cu-5, and Cu-8 had disordered thiophene moieties that were refined in two partial occupancy positions. Cell indexing, data collection, integration, structure solution, and refinement were performed using Bruker and Shelxtl software. Details will be published elsewhere.

[0156] 2-Bromoethyl phenyl sulfide (PhSCH ₂ CH ₂ Br), 2-bromoethyl methyl sulfide (MeSCH ₂ CH ₂ Br), 2-bromoethyl benzyl sulfide (BnSCH ₂ CH ₂ Br), and 3-bromopropyl benzyl sulfide (BnCH ₂ CH ₂ CH ₂ Br) were prepared as described below, and shown in Scheme 1.

[0157] Synthesis of 2-bromoethyl phenyl sulfide (CAS Number 4837-01-8). 2- (phenylthio)ethanol (30 ml, 0.222 mol) was cooled using an ice bath. Phosphorus tribromide (7.1 ml, 0.076 mol) was carefully added dropwise to the now cold 2-(phenylthio)ethanol with stirring over the period of 15 min (the reaction is exothermic). The resulting solution was stirred at room temperature for another 30 min. The reaction was partitioned between 100 ml of ether and 50 ml of water. The organic phase was separated, dried over MgSCM, filtered and the solvent was removed by evaporation to give 44.7 g of the crude product, which was then purified by vacuum distillation. Yield: 43.6 g (91%).

[0158] Synthesis of 2-bromoethyl methyl sulfide (CAS Number 54187-93-8).

Phosphorus tribromide (6.6 ml, 0.070 mol) was carefully added dropwise to 2- (methylthio)ethanol with stirring (19.39 g, 0.210 mol) over the period of 60 min (the reaction is exothermic, so a 4°C ice-bath was used). To the resulting viscous mixture was added diethyl ether (75 ml) and then water (15 ml). The ice-bath was removed and the mixture was allowed to stir for approximately 1 min to afford two clear phases. The organic phase was separated (top of the separating funnel), dried over MgSCM, filtered and solvent was removed by evaporation to give 9.79 g of the crude product, which was then purified by vacuum distillation. Yield: 7.51 g (23%), transparent liquid.

[0159] Synthesis of 2-bromoethyl benzyl sulfide (CAS Number 60671-59-2). A neat mixture of benzyl bromide (25 grams, 17.4 ml, 0.108 mol) and ethylene sulfide (10.96 grams, 10.9 ml, 0.182 mol) was prepared and heated to 50°C while being monitored by 1H NMR spectroscopy for the disappearance of the benzyl bromide methylene proton signal at δ 4.53 ppm (cf. 3.79 ppm resonance of the product in CDC1 ₃ ). Less than 7%> was present after 24 hours, and less than 2% was present after 48 hours. After reacting for 65 hours, the solution was flushed with dry argon to remove excess ethylene sulfide (70°C, 20 min). The product was purified by distillation under vacuum. The first fraction that boiled at 50°C was collected. This fraction solidified during the distillation. Yield: 30.49 g (90%). After several weeks, the product solidified under air in the refrigerator. It therefore is recommended to use it immediately or within the first week for synthetic chemistry.

[0160] Synthesis of 3-bromopropyl benzyl sulfide (CAS Number 88738-51-6).

A mixture of trimethylene sulfide (7.09 grams, 0.096 mol) and benzyl bromide (10.4 ml, 0.088 mol) dry acetonitrile (45 mL) was stirred at room temperature for 26 hours. The acetonitrile was evaporated at reduced pressure (55°C, 1 h, 40 mbar) and the residue distilled in vacuo to yield 18.9 g (88%>) of a colorless oil containing 3-bromopropyl benzyl sulfide with approximately 6%> of BnBr.

[0161] Synthesis of diphenylvinylphosphine oxide (CAS Number 2096-78-8). To a solution of 25 g of diphenylvinylphosphine in 1000 ml of dichloromethane was added dropwise a solution of Η ₂ 0 ₂ (30 ml, 30 wt .%> in H ₂ 0, reagent) in water (100 ml) under stirring overnight. After completion of the reaction as verified by ³¹ P{ ¹ H} NMR monitoring, to the mixture was added 1000 ml water and organic phase was separated. It was washed with water two times (1000 ml), dried over MgS0 ₄ , filtered and evaporated to afford the product in 87%> yield (white solid, 23.38 g).

[0162] Example 2. Synthesis of NNS-Type Ligands

[0163] Chart 1 below illustrates the NNS-type ligands of the general formula

(E)N(CH ₂ ) _m NH(CH ₂ )„SRi that were synthesized and subsequently used to make embodiment complexes.

Chart 1

[0164] Ligands la, lb, lc, Id, le, 2a, 3a, 4a, 4b, and 5a were synthesized according to Scheme 1. The reactions were performed in air inside a fume hood. These ligands are colorless or yellow liquids and were characterized via elemental analysis, 1H and ¹³ C{ ¹ H} NMR spectroscopy.

e 4b: R ^: Bn, y. 53%

NH,

K ₂ C0 ₃ , MeCN, 40 h, reflux

2a: y. 34%

2d: . 10% ^c

5a: y. 60%

Scheme 1. Synthesis of NN(H)S-type ligands 1-5 of the general formula

(E)N(CH ₂ ) _m NH(CH ₂ )„SRi: Isolated yields after fractional or simple (ligand 5a) vacuum distillations. ^a Contains ~6% BnBr. ^b Crude yield in the 21 :79 mixture with 2-(4-(2- (phenylthio)ethyl)piperazin-l-yl)ethanamine. ^c Synthesis was performed only one time.

[0165] Example 2.1. Synthesis of ligand la (2-morpholino-N-(2- phenylthio)ethyl)ethylamine) . K ₂ C0 ₃

MeCN

reflux, 16 h

16% 68% 16%

1 a

Scheme 2. Analysis of the N-Alkylation reaction by NMR after filtering the reaction mixture and further solvent evaporation.

[0166] To a solution of 2-(4-morpholinyl)ethanamine (13.1 ml, 0.1 mol) in acetonitrile (200 mL) were added successively 2-bromoethyl phenyl sulfide (15.1 ml, 0.1 mol) and anhydrous potassium carbonate (38.9 g, 0.28 mol) with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, filtered (the residue on the filter was washed with acetonitrile, 2 x 15 ml) and the solvent was removed by evaporation on a rotavap to afford 24.78 g of a viscous yellow oil (55 °C, 1 h, 40 mbar). 1H NMR specroscopy performed on the oil revealed a mixture of three amines: the starting 2-morpholinoethylamine (16%), the desired product, 2-morpholino-N-(2-(phenylthio)ethyl)ethylamine (68%) and t2-morpholino-N,N-bis(2- (phenylthio)ethyl)ethylamine (16%>) as shown in Scheme 2. The desired product was obtained by fractional vacuum distillation on a simple distillation kit without theoretical plates. The first collected fraction that boiled at 35 - 39 °C corresponds to residual 2-(4-morpholinyl)ethanamine (recovery 1.97 g, ~ 2 ml, transparent liquid). The second collected fraction that boiled at 145 - 167 °C corresponds to the desired product. Isolated yield: 15.45 g (58%>, based on 2-bromoethyl phenyl sulfide) as a clear yellowish oil. Elem. Anal: Calcd for C14H22N2OS (266.40): C, 63.12;

H, 8.32; N, 10.52%; Found: C, 63.04; H, 8.22; N, 10.42%. ¹ H NMR (400 MHz, CDC1 ₃ , r.t.): δ

I .77 (brs, 1H, NH), 2.43 (vt, ³ J _H - _H ~ 5 Hz, 4H), 2.48 (t, ³ J _H - _H = 6 Hz, 2H), 2.70 (t, ³ J _H - _H = 6 Hz, 2H), 2.86 (t, ³ JH-H = 6 Hz, 2H), 3.08 (t, ³ J _H - _H = 6 Hz, 2H), 3.70 (t, ³ J _H - _H ~ 5 Hz, 4H), 7.19 (t, ³ J _H - H ~ 7 Hz, lH^ _ra ), 7.28 (t, ³ J _H - _H ~ 8 Hz, 2H _meta ), 7.36 (d, ³ J _H - _H ~ 8 Hz, 2H _ortho ). ¹³ C{1H} (100.5 MHz, CDCI ₃ , r.t.): δ 34.1 (s, 1C), 45.7 (s, 1C), 48.4 (s, 1C), 53.7 (s, 2C), 58.3 (s, 1C), 67.0 (s, 2C), 126.2 (s, \C _para , Ph), 128.9 (s, 2C _ortho , Ph), 130.0 (s, 2C _meta , Ph), 135.9 (s, lC^).

[0167] Example 2.2. Synthesis of ligand lb (3-morpholino- V-(2- (phenylthio)ethyl)propan-l-amine). A solution of 3-morpholinopropylamine (14.6 ml, 0.1 mol) in acetonitrile (200 mL) was prepared. 2-bromoethyl phenyl sulfide (15.1 ml, 0.1 mol) was added to the solution with stirring, followed by anhydrous potassium carbonate (38.9 g, 0.28 mol) also with stirring. The resulting suspension was refluxed for 16 hours, cooled to room temperature, and filtered. The residue on the filter was washed with acetonitrile, 2 x 15 ml, and the solvent was removed by evaporation on a rotavap to afford 27.6 g of a viscous yellow oil (55 °C, 1 h, 40 mbar). Ligand lb was obtained by fractional vacuum distillation on a simple distillation kit containing two theoretical plates. The first collected fraction that boiled at 41 - 46°C corresponds to residual 3-morpholinopropylamine (recovery ~ 2.8 ml, transparent liquid). The second collected fraction that boiled at 141 - 156°C corresponds to ligand lb (isolated yield: 15.98 g (57%, based on 2-bromoethyl phenyl sulfide) as a clear almost transparent (slightly yellowish) oil. Elem. Anal: Calc'd for Ci ₅ H ₂ 4N ₂ OS (280.43): C, 64.25; H, 8.63; N, 9.99%; Found: C, 64.13; H, 8.88; N, 9.99%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.56 (brs, 1H, NH), 1.64 (q, ³ J _H - _H ~ 7 Hz, 2H), 2.36 (t, ³ J _H - _H = 8 Hz, 2H), 2.40 (brs, 4H), 2.63 (t, ³ J _H - _H = 7 Hz, 2H), 2.82 (t, ³ J _H - _H = 7 Hz, 2H), 3.05 (t, ³ J _H _ _H = 7 Hz, 2H), 3.69 (t, ³ J _H _ _H ~ 4 Hz, 4H), 7.16 (t, ³ J _H _ _H ~ 7 Hz, _para ), 7.26 (t, JH-H ~ 8 Hz, 2U _meta ), 7.34 (d, ³ J _H - _H ~ 7 Hz, 2U _ortho ). ¹³ C{1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 26.7 (s, 1C), 34.2 (s, 1C), 48.1 (s, 1C), 48.3 (s, 1C), 53.8 (s, 2C), 57.3 (s, 1C), 67.0 (s, 2C), 126.1 (s, l Cpara, Ph 128.9 (s, 2C _orth o, Ph 129.6 (s, 2C _meta , Ph), 135.9 (s, 1C^ ₀ ).).

[0168] Example 2.3. Synthesis of ligand lc (2-(phenylthio)- V-(2-(pyrrolidin-l- yl)ethyl)ethylamine). A solution of l-(2-aminoethyl)pyrrolidine (4.57 g, 0.04 mol) in acetonitrile (80 mL) was prepared. 2-bromoethyl phenyl sulfide (8.70 g, 0.04 mol) was added to the solution, followed by anhydrous potassium carbonate (15.20 g, 0.11 mol), with stirring. The resulting suspension was refluxed for 16 hours, cooled to room temperature, filtered (the filter was washed with acetonitrile 2 x 10 ml) and the solvent was removed by evaporation on a rotavap to afford 9.72 g of a viscous orange-yellow oil (60 °C, 1 h). Ligand lc was obtained by fractional vacuum distillation on a simple distillation kit containing two theoretical plates. The first collected fraction boiled at 26 - 28°C and corresponds to residual l-(2- aminoethyl)pyrrolidine (recovery approximately 1 ml). The second collected fraction boiled at 130 - 142 °C and corresponds to ligand lc. Isolated yield: 4.94 g (49%>, based on 2-bromoethyl phenyl sulfide) of a clear yellowish oil. Elem. Anal: Calc'd for Ci ₄ H ₂₂ N ₂ S (250.40): C, 67.15;

H, 8.86; N, 11.19%; Found: C, 66.88; H, 8.59; N, 10.79%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ

I .67 (brs, 1H, NH), 1.78 (brs, 4Η), 2.50 (brs, 4Η), 2.59 (t, ³ J _H _ _H = 6 Hz, 2H), 2.74 (t, ³ J _H _ _H = 6 Hz, 2H), 2.88 (t, ³ JH-H ~ 6 Hz, 2H), 3.08 (t, ³ J _H - _H ~ 6 Hz, 2H), 7.19 (t, ³ J _H - _H ~ 7 Hz, lH^ _ra ), 7.29 (t, JH-H ~ 8 Hz, 2H _meta ), 7.37 (d, JH-H ~ 8 Hz, 2H _ortho ). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 23.5 (s, 2C), 34.2 (s, 1C), 48.3 (s, 1C), 48.6 (s, 1C), 54.2 (s, 2C), 56.0 (s, 1C), 126.1 (s, lC^ _ra , Ph), 128.9 (s, ICortho, Ph), 130.0 (s, 2C _met a, Ph), 136.0 (s, 1C^ ₀ ).

[0169] Example 2.4. Synthesis of ligand Id ( V , V -dimethyl- V ² -(2- (phenylthio)ethyl)ethane-l,2-diamine). To a solution of N,N-dimethylethylenediamine (10.9 ml, 0.1 mol) in acetonitrile (200 mL) were added successively 2-bromoethyl phenyl sulfide (15.08 ml, 0.1 mol) and anhydrous potassium carbonate (38.9 g, 0.28 mol) with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, filtered (the filter was washed with acetonitrile 2 x 15 ml) and the solvent was removed by evaporation on rotavap to afford 18.54 g of the viscous yellowish oil (60 °C, 1 h). The desired product was obtained by fractional vacuum distillation on a simple distillation kit containing two theoretical plates. The first collected fraction that boiled at 30 - 33 °C corresponds to N,N-dimethylethylenediamine (recovery ~ 2.9 ml). The second collected fraction that boiled at 90 - 1 10 °C corresponds to the desired product. Isolated yield: 1 1.22 g (50%, based on 2-bromoethyl phenyl sulfide) as a clear, almost transparent (slightly yellowish) oil. Elem. Anal.: Calcd for C12H20N2S (224.37): C, 64.24;

H, 8.99; N, 12.49%; Found: C, 64.19; H, 8.87; N, 12.46%.1H NMR (400 MHz, CDC1 ₃ , r.t.): δ

I .83 (brs, 1H, NH), 2.19 (s, 6Η), 2.37 (t, ³ J _H _ _H = 6 Hz, 2H), 2.65 (t, ³ J _H _ _H = 6 Hz, 2H), 2.83 (t, JH-H ~ 7 Hz, 2H), 3.04 (t, ³ J _H _ _H ~ 7 Hz, 2H), 7.15 (t, ³ J _H _ _H ~ 7 Hz, m _para ), 7.25 (t, ³ J _H _ _H ~ 8 Hz, 2U _meta ), 7.33 (d, JH-H ~ 8 Hz, 2U _ortho ). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 34.1 (s, 1C), 45.5 (s, 2C), 47.0 (s, 1C), 48.6 (s, 1C), 59.1 (s, 1C), 126.1 (s, \C _para , Ph), 128.9 (s, 2C _ortho , Ph), 130.0 (s, 2C _meta , Ph), 136.0 (s, lC _ipso ).

[0170] Example 2.5. Synthesis of ligand le (2-(phenylthio)- V-(2-(piperazin-l- yl)ethyl)ethanamine). A solution of l-(2-aminoethyl)piperazine (13.1 ml, 0.1 mol) in acetonitrile (200 mL) was prepared. 2-bromoethyl phenyl sulfide (15.1 ml, 0.1 mol) was added to the solution, followed by anhydrous potassium carbonate (38.9 g, 0.28 mol), with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, and filtered. The residue on the filter was washed with acetonitrile, 2 x 15 ml, and the solvent was removed by

evaporation on a rotavap to afford 25.45 g of a viscous orange liquid (55°C, 1 h, 40 mbar). Two fractions were distilled from this mixture. The first collected fraction boiled at 43 - 48°C and corresponds to residual l-(2-aminoethyl)piperazine (recovery ~ 4.3 ml, transparent liquid). The second collected fraction boiled at 152 - 173°C and corresponds to a mixture of 2-(4-(2- (phenylthio)ethyl)piperazin- 1 -yl)ethanamine and 2-(phenylthio)-N-(2-(piperazin- 1 - yl)ethyl)ethanamine in a 1 :0.27 ratio (8.36 g, yellow oil) according to 1H NMR Analysis. No further purification was performed.

[0171] Example 2.6. Synthesis of ligand 2a (2-(methylthio)- V-(2- morpholinoethyl)ethanamine). Method A (from MeSCH ₂ CH ₂ Br). A solution of 2-(4- morpholinyl)ethanamine (5.87 ml, 0.045 mol) in acetonitrile (90 mL) was prepared. 2- bromoethyl methyl sulfide (6.94 g, 0.045 mol) was added to the solution, followed by anhydrous potassium carbonate (17.4 g, 0.13 mol), with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, filtered (the residue on the filter was washed with acetonitrile, 2 x 10 ml) and the solvent was removed by evaporation on a rotavap to afford 9.06 g of a yellow suspension (55°C, 1 h, 40 mbar). Ligand 2a was obtained by fractional vacuum distillation on a simple distillation kit without theoretical plates. The first collected fraction boiled at 30 - 31°C and presumably corresponds to residual 2-(4-morpholinyl)ethanamine (recovery was

approximately 1.6 ml, transparent liquid). The second collected fraction boiled at 91 - 1 15°C and corresponds to ligand 2a. Isolated yield: 3.50 g (38%, based on 2-bromoethyl methyl sulfide) as a transparent liquid. A note of caution: a higher boiling fraction (> 1 15°C) contains an admixture of tertiary amine. Elem. Anal: Calc'd for C ₉ H ₂₀ N ₂ OS (204.33): C, 52.90; H, 9.87; N, 13.71%; Found: C, 52.98; H, 9.90; N, 13.53%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 2.08 (s, 3H), 2.18 (brs, 1H, NH), 2.42 (m, 4H), 2.48 (t, ³ J _H - _H = 6 Hz, 2H), 2.64 (t, ³ J _H - _H = 6 Hz, 2H), 2.71 (t, ³ J _H - _H = 6 Hz, 2H), 2.82 (t, ³ J _H H = 6 Hz, 2H), 3.68 (vt, ³ J _{H H} ~ 5 Hz, 4H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 15.3 (s, 1C), 34.3 (s, 1C), 45.7 (s, 1C), 48.0 (s, 1C), 53.7 (s, 2C), 58.2 (s, 1C), 67.0 (s, 2C).

[0172] Example 2.7. Synthesis of ligand 2a (2-(methylthio)- V-(2- morpholinoethyl)ethanamine). Method B (from MeSCH ₂ CH ₂ Cl). This method was similar to Method A above, but 2-chloroethyl methyl sulfide was used instead of 2-bromoethyl methyl sulfide and the reaction mixture was refluxed for 40 h instead of 16 h. Isolated yield of ligand 2a: 3.13 g (34% from 5 g of MeSCH ₂ CH ₂ Cl). Elem. Anal : Calc'd for C ₉ H ₂₀ N ₂ OS (204.33): C, 52.90; H, 9.87; N, 13.71%; Found: C, 52.82; H, 10.03; N, 13.50%.

[0173] Example 2.8. Synthesis of ligand 2d ( V , V -dimethyl- V ² -(2- (methylthio)ethyl)ethane-l,2-diamine). To a solution of N,N-dimethylethylenediamine (4.94 ml, 0.045 mol) in acetonitrile (90 mL) were added successively 2-chloroethyl methyl sulfide (5 g, 0.045 mol) and anhydrous potassium carbonate (17.7 g, 0.13 mol) with stirring. The resulting suspension was refluxed for 40 h, cooled to room temperature, filtered (the filter was washed with acetonitrile 2 x 10 ml) and the solvent was removed by evaporation on a rotavap to afford 5.5 g of the yellowish liquid (60 °C, 1 h). The desired product was obtained by slow fractional vacuum distillation. The first collected fraction that boiled at 25 - 40 °C corresponds to the 1 :2 mixture of starting N ^; ,N ^; -dimethylethylenediamine and the desired product (recovery ~ 1 ml). The second collected fraction that boiled at 40 - 70 °C corresponds to the pure desired product. Isolated yield: 0.75 g (10%, based on 2-chloroethyl methyl sulfide) as a clear, almost transparent (slightly yellowish) oil. The fraction that boiled > 70 °C corresponds to the mixture of products. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.58 (brs, 1H, NH), 2.06 (s, 3Η), 2.18 (s, 6Η), 2.09 (t, ³ J _H - _H ~ 6 Hz, 2H), 2.61 (t, ³ J _{H H} ~ 7 Hz, 2H), 2.66 (t, ³ J _{H H} ~ 6 Hz, 2H), 2.80 (t, ³ J _{H H} ~ 7 Hz, 2H). ¹³ C{1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 15.3 (s, 1C), 34.3 (s, 1C), 45.6 (s, 2C), 47.0 (s, 1C), 48.3 (s, 1C), 59.2 (s, 1C).

[0174] Example 2.9. Synthesis of ligand 3a (2-morpholino-7V-(2- (benzylthio)ethyl)ethylamine). A solution of 2-morpholinoethylamine (6.56 ml, 0.05 mol) in acetonitrile (100 mL) was prepared. 2-bromoethyl benzyl sulfide (11.56 g, 0.05 mol) was added to the solution, followed by anhydrous potassium carbonate (19.35 g, 0.14 mol), with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, and filtered. The residue on the filter was washed with acetonitrile 2 x 10 ml, and the solvent was removed by evaporation on a rotavap to afford 13.75 g of a viscous orange-yellow suspension (55 °C, 1 h, 40 mbar). Ligand 3a was obtained by fractional vacuum distillation on Vigreux column composed of two theoretical plates. The first collected fraction boiled at 34 - 38°C and corresponds to the residual 2-(4-morpholinyl)ethanamine (recovery 1.64 g, approximately 1.7 ml). The second collected fraction boiled at 132 - 158°C and corresponds to ligand 3a. Isolated yield: 4.81 g (34%, based on 2-bromoethyl benzyl sulfide) of a clear dark-yellowish oil. Elem. Anal.: Calc'd for Ci ₅ H ₂₄ N ₂ OS (280.43): C, 64.25; H, 8.63; N, 9.99%; Found: C, 64.44; H, 8.33; N, 10.23%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.88 (brs, 1H, NH), 2.43 (brm, 4Η), 2.46 (t, ³ J _H - _H = 6 Hz, 2H), 2.59 (t, JH-H = 6 Hz, 2H), 2.66 (t, ³ J _H - _H ~ 7 Hz, 2H), 2.77 (t, ³ J _H - _H ~ 7 Hz, 2H), 3.70 (t, ³ J _H - _H ~ 7 Hz, 4H), 3.72 (s, 2H), 7.20-7.31 (m, 5H). ¹³ C{1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 31.7 (s, 1C), 36.2 (s, 1C), 45.7 (s, 1C), 48.4 (s, 1C), 53.8 (s, 2C), 58.3 (s, 1C), 67.0 (s, 2C), 127.0 (s, lC^ _ra , Ph), 128.5 (s, 2C _meta , Ph), 128.8 (s, 2C _ortho , Ph), 138.5 (s, lC^).

[0175] Example 2.10. Synthesis of ligand 4a (3-(benzylthio)- V-(2- morpholinoethyl)propan-l-amine). A solution of 2-(4-morpholinyl)ethanamine (3.4 ml, 0.026 mol) in acetonitrile (50 mL) was prepared. 3-bromopropyl benzyl sulfide (6.36 g, 0.026 mol) was added to the solution, followed by anhydrous potassium carbonate (10 g, 0.072 mol), with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, and filtered. The residue on the filter was washed with acetonitrile 2 x 10 ml, and the solvent was removed by evaporation on a rotavap to afford 7.15 g of a viscous orange-yellow liquid (55°C, 1 h, 40 mbar). Ligand 4a was obtained by fractional vacuum distillation on Vigreux column composed of two theoretical plates. The first collected fraction boiled at 25 - 26°C and corresponds to residual 2-(4-morpholinyl)ethanamine (recovery approximately 0.5 ml). The second collected fraction boiled at 145 - 176 °C and corresponds to the analytically pure ligand 4a (3.57 g, 47%, based on 3-bromopropyl benzyl sulfide). Elem. Anal: Calc'd for Ci ₆ H ₂ 6N ₂ OS (294.46): C, 65.26; H, 8.90; N, 9.51%; Found: C, 65.56; H, 9.08; N, 9.75%. 1H NMR (400 MHz, CDCls, r.t.): δ 1.42 (brs, 1H, NH), 1.75 (q, J= 7 Hz, 2H), 2.35-2.53 (overlapped m, 8H), 2.66 (t, ³ JH-H = 7 Hz, 4H), 3.65-3.73 (overlapped m, 6H), 7.23 (m, 1H), 7.26-7.35 (overlapped m, 4H). ¹³ C{1H} (100.5 MHz, CDCI ₃ , r.t.): δ 29.2 (s, 1C), 29.5 (s, 1C), 36.3 (s, 1C), 46.1 (s, 1C), 48.9 (s, 2C), 53.8 (s, 1C), 58.3 (s, 2C), 67.0 (S, 1C), 126.9 (s, lC^ _ra , Ph), 128.4 (s, 2C _meta , Ph), 128.8 (s, 2C _ortho , Ph), 138.5 (s, lCipso).

[0176] Example 2.11. Synthesis of ligand 4b (3-(benzylthio)- V-(3- morpholinopropyl)propan-l-amine). To a solution of 3-morpholinopropylamine (4.64 ml, 0.03 mol) in acetonitrile (65 mL) were added successively 3-bromopropyl benzyl sulfide (7.78 g, 0.03 mol) and anhydrous potassium carbonate (12.40 g, 0.09 mol) with stirring. The resulting suspension was refluxed for 16 h, cooled to room temperature, filtered (the residue on the filter was washed with acetonitrile 2 x 10 ml) and the solvent was removed by evaporation on a rotavap to afford 9.49 g of a yellow solution containing a small amount of a yellow solid (55 °C, 1 h, 40 mbar). The desired product was obtained by fractional vacuum distillation on small Vigreux column composed of two theoretical plates. The first collected fraction that boiled at 33 - 35 °C corresponds to the residual 3-morpholinopropylamine (recovery ~ 0.8 ml). The second collected slightly yellowish fraction that boiled at 148 - 173 °C corresponds to the desired product (4.22 g). A yellow fraction that boiled at 173 - 185 °C was also collected and corresponds to the desired product according to NMR analysis (0.68 g). Combined isolated yield: 4.9 g (53%, based on 3-bromopropyl benzyl sulfide) of a clear yellowish oil. Elem. Anal: Calcd for Ci ₇ H ₂₈ N ₂ OS (308.48): C, 66.19; H, 9.15; N, 9.08%; Found: C, 65.79; H, 9.19; N, 9.13%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.56 (brs, 1H, NH), 1.64 (q, ³ J _H - _H = 7 Hz, 2H), 1.72 (q, ³ J _H - _H = 7 Hz, 2H), 2.32-2.47 (overlapped m, 8H), 2.57-2.68 (overlapped m, 4H), 3.67 (overlapped m, 6H), 7.21 (m, 1H), 7.24-7.32 (overlapped m, 4H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 26.7 (s, 1C), 29.2 (s, 1C), 29.4 (s, 1C), 36.3 (s, 1C), 48.5 (s, 1C), 48.8 (s, 1C), 53.8 (s, 2C), 57.4 (s, 1C), 67.0 (s, 2C), 126.9 (s, \C _pam , Ph), 128.4 (s, 2C _meta , Ph), 128.8 (s, 2C _ortAo , Ph), 138.5 (s, \C _ipso ).

[0177] Example 2.12. Synthesis of ligand 5a (2-morpholino- V-(thiophen-2- ylmethyl)ethanamine). To a solution of 2-(4-morpholinyl)ethanamine (5 g, 5.1 ml, 0.038 mol) in methanol (80 ml) was added freshly distilled thiophenecarbaldehyde (3.6 ml, 0.038 mol). The obtained mixture was stirred for 24 h to afford a yellow solution, to which was slowly added NaBH ₄ (4 equiv, 5.8 g, 20 min), resulting in hydrogen evolution, then 10 ml of methanol (to pick up the remaining NaBH ₄ from the funnel) and the system was stirred for 20 h at room

temperature. To the white suspension was slowly added 30 ml H ₂ 0 and then 100 ml CH ₂ C1 ₂ . The organic phase was extracted. The residual inorganic phase was washed with 100 ml CH ₂ C1 ₂ . The combined phases afforded the crude product as a yellow liquid after solvent evaporation (7.08 g). The product was purified by vacuum distillation (109-1 13 °C). Isolated yield: 5.20 g (60%>), transparent oil. Elem. Anal : Calcd for CnHi ₈ N ₂ OS (226.34): C, 58.37; H, 8.02; N, 12.38%; Found: C, 58.13; H, 8.20; N, 12.41%.1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 2.1 1 (brs, 1H, NH), 2.40 (m, 4Η), 2.49 (t, ³ J _H - _H = 6 Hz, 2H), 2.73 (t, ³ J _H - _H = 6 Hz, 2H), 3.68 (m, 4H), 4.01 (s, 2H), 6.89-6.96 (m, 2H), 7.20 (dd, ³ J _H - _H ~ 5 Hz, ⁴ J _H - _H ~ 1 Hz, 1H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 44.9 (s, 1C), 48.3 (s, 1C), 53.7 (s, 2C), 58.1 (s, 1C), 67.0 (s, 2C), 124.4 (s, 1C), 125.0 (s, 1C), 126.6 (s, 1C), 144.1 (s, 1C).

Chart 2 below illustrates the NNS-type ligands of the formula

E(CH ₂ ) ₃ N(CH ₃ )(CH ₂ ) ₃ SBn (E = -NC ₄ H ₈ 0 and -N(CH ₃ ) ₂ ) that were synthesized, isolated and subsequently used to make embodiment complexes. Chart 2

E(CH ₂ )3N(CH ₃ )(CH ₂ ) ₃ SBn (E = -NC ₄ H ₈ 0 and -N(CH ₃ ) ₂ ): isolated yields are shown.

[0178] Example 2.13. Synthesis of ligand 6 (3-(benzylthio)- V-methyl- V-(3- morpholinopropyl)propan-l-amine). A mixture of 4b (1.19 g, 3.858 mmol), formic acid (712 mg, 4 equiv) and 1.75 mL of formaldehyde solution (37 wt. % in H ₂ 0) was stirred for 2 h at 100 °C in a 50 ml schlenk flask in air. The reaction mixture was cooled, treated with 18 mL of a 20% aqueous solution of NaOH and extracted with 3 x 20 mL of Et ₂ 0. The combined ether solution was washed with 2 x 20 mL of water, dried over MgS0 ₄ , filtered and evaporated under vacuum on a rotavap (55 °C, 1 h, 40 mbar). Yield: 0.99 g (80 %), yellowish liquid. Elem. Anal : Calcd for Ci ₈ H ₃₀ N ₂ OS (322.51): C, 67.04; H, 9.38; N, 8.68%; Found: C, 67.89; H, 9.45; N, 8.77%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.64 (q, ³ J _H - _H = 7 Hz, 2H), 1.71 (q, ³ J _H - _H = 7 Hz, 2H), 2.19 (s, 3H), 2.30-2.50 (overlapped m, 12H), 3.71 (overlapped m, 6H), 3.67 (overlapped m, 6H), 7.23 (m, 1H), 7.26-7.34 (overlapped m, 4H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 24.4 (s, 1C), 26.9 (s, 1C), 29.3 (s, 1C), 36.4 (s, 1C), 42.2 (s, 1C), 53.8 (s, 2C), 55.6 (s, 1C), 56.5 (s, 1C), 57.0 (s, 1C), 67.0 (s, 2C), 126.9 (s, \C _pam , Ph), 128.5 (s, 2C _meta , Ph), 128.8 (s, 2C _ortAo , Ph), 138.5 (s,

1 Cipso■

[0179] Example 2.14. Synthesis of ligand 7 (3-(benzylthio)- V -methyl- V ² , V ² - dimethyl)propan-l-amine). A solution of A ,A ,N'-trimethyl-l ,3-propanediamine (96% Aldrich, 5 g, 0.043 mol) in acetonitrile (90 mL) was prepared. 3-bromopropyl benzyl sulfide (10.54 g, 0.043 mol) was added to the solution, followed by anhydrous potassium carbonate (16.5 g, 0.12 mol), with stirring. The resulting suspension was refluxed for 16 hours, cooled to room temperature, and filtered. The residue on the filter was washed with acetonitrile (2 x 10 ml) and the solvent was removed by evaporation on a rotavap to afford 1 1.89 g of a two-phase yellow liquid (55 °C, 1 h, 40 mbar). The desired product was obtained by fractional vacuum distillation on a simple distillation kit without theoretical plates. The first collected transparent fraction that boiled at 75 - 135°C corresponds to desired product. Isolated yield: 3.25 g (27%) as a clear liquid. Elem. Anal : Calcd for Ci ₆ H ₂ 8N ₂ S (280.47): C, 68.52; H, 10.06; N, 9.99%; Found: C, 68.15; H, 9.99; N, 9.70%. 1H NMR (400 MHz, CDC13, r.t.): δ 1.60 (q, 3JH-H ~ 7 Hz, 2H), 1.69 (s, 3JH-H ~ 7 Hz, 2H), 2.17 (s, 3H), 2.20 (s, 6H), 2.24 (vt, J ~ 7 Hz, 2H), 2.32 (vt, J ~ 7 Hz, 2H), 2.36 (vt, J ~ 7 Hz, 2H), 2.42 (vt, J ~ 7 Hz, 2H), 3.69 (s, 2H), 7.21 (m, 1H), 7.24-7.32 (m, 4H). 13C { 1H} (100.5 MHz, CDC13, r.t.): δ 25.7 (s, 1C), 27.0 (s, 1C), 29.3 (s, 1C), 36.3 (s, 1C), 42.3 (s, 1C), 45.6 (s, 2C), 55.8 (s, 1C), 56.6 (s, 1C), 57.9 (s, 1C), 126.9 (s, 1C), 128.4 (s, 2C), 128.8 (s, 2C), 138.6 (s, 1C).

[0180] Example 3. Synthesis of P(Q)NS-type and PNS -Type Ligands

P(0)NS-type and PNS ligands of the type shown in Chart 3 can be or have been prepared and used to make inventive complexes.

Chart 3.

[0181] Ligand 8 was synthesized from diphenylvinylphosphine oxide according to Scheme 4. The reaction was performed in air inside a fume hood. The corresponding phosphine Ligand 8* may be prepared by reduction with a variety of reducing agents, including silanes as shown in Scheme 4 (argon). Such processes are well-documented in literature (see, e.g., Curr. Green Chem., 2014, 1, 182; Org. Lett. 2004, 6, 4675, incorporated by reference herein).

[0182] Example 3.1. Synthesis of ligand 8 [(2-((2- (methylthio)ethyl)amino)ethyl)diphenylphosphine oxide] . Isolation of 8 and 9.

yellowish oil white solid

8 9

Scheme 5.

[0183] A mixture of diphenylvinylphosphine oxide (lg, 4.38 mmol) and 2- (methylthio)ethylamine (1.1 equiv, 448 mkl, 4.82 mmol, 97% Aldrich) were stirred in 10 ml of water at 100 °C for 6 h. When stirring was switched off, two phases were clearly observed: orange organic phase and transparent water phase. The organic phase was extracted with dichloromethane (2 x 15 ml), combined extracts were dried over MgSC^ and the solvent was removed on rotavapor (1 h, 60 °C) to afford the crude product as a yellow-orange viscous oil primarily comprising a mixture of product 8 (>88%), tertiary amine (>9%) and traces of starting material (δ 28.0 ppm) according to ³¹ P{ ¹ H} NMR (1250 mg). The crude product could be directly used in the synthesis of trarcs-[Ru ⁿ Cl ₂ {K ³ (,S;N' <3)-8}(PPh ₃ )] (D-l), vide infra.

Alternatively, the crude product was purified by column (8.5 x 5 cm) chromatography (Si0 ₂ 230-400 mesh, 40 - 63 μ, av. pore diameter 60 A, Sigma, ca. 120 g, CHCl ₃ /methanol, 100: 13, ca. 500 ml of the binary mixture; R = 0.31 for the product, Ry= 0.63 for the tertiary amine, TLC Baker-Flex silicagel IB-F). First fraction: tertiary amine, yield after washing with pentane under stirring (2 x 10 ml): 111 mg, of an off-white solid as shown in Scheme 5. Second fraction: product yield after solvent evaporation and drying (2 h, 60 °C) : 1082 mg (78%), transparent yellowish oil as shown in Scheme 5. Characterization data for ligand 8. Elem. Anal.: Calcd for C17H22NOPS (319.40): C, 63.93; H, 6.94; N, 4.39%; Found: C, 62.41; H, 6.98; N, 4.39%. 31P{1H} (162 MHz, CDC13, rt): δ 30.8 (s). 1H NMR (400 MHz, CDC13, 25 °C): δ 1.83 (brs, 1H, NH), 2.08 (s, 3H, SMe), 2.51-2.57 (m, 2H), 2.60 (vt, J ~ 7 Hz, 2H), 2.79 (vt, J ~ 7 Hz, 2H), 2.99 (m, 2H), 7.47-7.56 (m, 6H), 7.74-7.79 (m, 4H). 13C{1H} (100.5 MHz, CDC13, 25 °C): δ 15.3 (s, 1C), 30.5 (d, JC-P = 71 Hz, 1C), 34.2 (s, 1C), 42.6 (s, 1C), 47.8 (s, 1C), 128.7 (d, JC-P = 12 Hz, 4Cmeta, Ph), 130.7 (d, JC-P = 9 Hz, 4Cortho, PPh3), 131.8 (d, JC-P = 3 Hz, 2Cpara, Ph), 132.9 (d, JC-P = 99 Hz, 2Cipso). Characterization data for ligand 9. Elem. Anal.: Calcd for C ₃ iH ₃₅ N0 ₂ P ₂ S (547.63): C, 67.99; H, 6.44; N, 2.56%; Found: C, 67.87; H, 6.32; N, 2.49%. %. ³¹ P{1H} (162 MHz, CDC1 ₃ , rt): δ 30.7 (s). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , 25 °C): δ 15.9 (s, 1C), 27.0 (d, Jc-P = 70 Hz, 2C), 31.8 (s, 1C), 45.6 (s, 2C), 56.9 (s, 1C), 128.7 (d, J _C - _P = 12 Hz, 8C _meto , Ph), 130.7 (d, Jc-P = 9 Hz, 8C _ortAo , PPh ₃ ), 131.8 (d, J _C _ _P = 3 Hz, 4C^ _ra , Ph), 133.0 (d, J _C _ _P = 99

Hz, C ipso)-

[0184] Example 4. Synthesis of NNS-type and SNNS -Type Chiral Ligands.

[0185] Chart 4 below illustrates the NNS-type (Ci-symmetry, ligands 10 and 11) and SNNS-Type (C ₂ -symmetry, ligands 12 and 12*) chiral Ligands of NNS-type and SNNS-type were synthesized, isolated and subsequently used to make inventive complexes.

Chart 4.

[0186] Ligands 10, 11 and 12 were synthesized according to Scheme 6. The reactions were performed in air inside a fume hood. Ligand 11* may be synthesized by using reduction of 11 with, for example, L1AIH ₄ as shown in Scheme 6.

12*

Scheme 6. Synthesis of NNS-type and SNNS-Type Chiral Ligands. Isolated yield after fractional vacuum distillation (ligands 10), column chromatography (ligand 11) or precipitation (ligand 12, crude), i: (R,R)-OACH (1 equiv) in H ₂ Q, r.t, 2 h; ii: NaBH ₄ (excess), dry EtOH, reflux, 24 h.

[0187] Example 4.1. Synthesis of ligand 10 ((/R,2R)-7Vl-(thiophen-2- ylmethyl)cyclohexane-l,2-diamine). A yellow solution of (i?,i?)-DACH (5 g, 43.79 mmol) in 20 ml of H ₂ 0 was added to 4.91 g (43.79 mmol) of freshly distilled 2-thiophenecarbaldehyde in one portion. The obtained mixture was vigorously stirred for 2 h. After this, the obtained white precipitate was filtered on a Buchner funnel, washed with water (5 x 10 ml) and then pentane (5 x 20 ml) and dried overnight under vacuum to afford a ~ 7:3 mixture of (H?,2R)-Nl-(thiophen-2- ylmethylene)cyclohexane-l ,2-diamine (1H NMR: δ 8.47 (1H), 7.41 (d, ³ J _H - _H = 4 Hz, 1H), 7.32 (d, ³ JH-H = 4 Hz, 1H), 7.09 (t, ³ J _H - _H = 4 Hz, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 1.94 (d, ³ J _H - _H = 1 1 Hz, 1H), 1.79 (m, 2H), 1.68 (m, 2H), 1.43-1.30 (m, 2H), 1.30-1.02 (m, 3H); ¹³ C {1H} NMR: δ 154.0, 142.5, 130.5, 128.7, 127.4, 77.9, 54.5, 33.7, 33.0, 25.1 , 24.8) and (1R,2R)-NI ,N2- bis(thiophen-2-ylmethylene)cyclohexane-l ,2-diamine (characteristic imine CH resonances at δ 8.29, 2H) containing traces of starting ( ?,i?)-DACH (< 6%, characteristic CH resonances at δ 2.27, 2H) according to 1H NMR analysis (total 7.6 g). The obtained mixture was refluxed with NaBH ₄ (7.7 g, ~5 equiv based on one C=N group) in 150 ml of dry EtOH for 24 h. The suspension was cooled to room temperature and H ₂ 0 (20 ml) was added to destroy excess NaBH ₄ . To the obtained mixture was added 80 ml of brine and 100 ml of CH ₂ C1 ₂ . The system was shaken, and the organic phase was separated on a separation funnel, washed with brine (3 x 80 ml), dried over anhydrous MgS0 ₄ , followed by filtration, then concentrated on a rotavap to give 6.88 g of a yellow-red liquid (1 h, 50 °C, 40 mbar). The final product was obtained after vacuum distillation from this liquid. A very small fraction corresponding to traces of (R,R)- DACH boiled at ~ 58 °C was precollected and solidified during distillation. The second fraction that boiled at 100 - 135 °C corresponds to the desired product (bath temperature 180 - 225 °C under a fully opened vacuum line). Isolated yield: 3.75 g of a clear, slightly yellowish oil (41% two-steps yield, based on (i?,i?)-DACH). Alternatively, if desired, the final product could be purified by column chromatography on silica gel (eluent CH ₂ Cl ₂ -MeOH-NH ₃ 10: 1 :0.5; R/= 0.36 for the desired product 9, R = 0.69 for the C ₂ -symmetric (H?,2R)- ,N2-bis(thiophen-2- ylmethyl)cyclohexane-l ,2-diamine). Elem. Anal : Calcd for CnHi ₈ N ₂ S (210.34): C, 62.81 ; H, 8.63; N, 13.32%; Found: C, 62.51 ; H, 8.43; N, 13.56%. 1H NMR (400 MHz, CDC1 ₃ , 25 °C): δ 0.95-1.32 (series of m, 4H), 1.55 (brs, 3H, NH), 1.70 (m, 2Η), 1.89 (d, J _H - _H = 12 Hz, 1H), 2.13 (m, 2H), 2.37 (m, 1H), 3.92 (d, ² J _H - _H ~ 14 Hz, 1H), 4.13 (d, ² J _H - _H ~ 14 Hz, 2H), 6.94 (m, 2H), 7.18 (m, 1H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , 25 °C): δ 25.2 (s, 1C), 31.4 (s, 1C), 35.9 (s, 1C), 45.7 (s, 1C), 55.4 (s, 1C), 124.1 (s, 1C), 124.3 (s, 1C), 126.5 (s, 1C), 145.3 (s, 1C).

[0188] Example 4.2. Synthesis of ligand 11 ((7R,2R)- Vl-(2-(phenylthio)ethyl)- V2- (thiophen-2-ylmethyl)cyclohexane-l,2-diamine). A solution of freshly prepared (phenylsulfanyl)acetaldehyde (668 mg, 4.39 mmol) in 7 ml of MeOH was added to a solution of 9 (922 mg, 4.38 mmol) in 5 ml of MeOH. The obtained mixture was stirred for 20 h to afford an orange (deep-red) solution. To this solution was slowly added NaBH ₄ (4 equiv, 663 mg) and the system was stirred for 7 h at room temperature. To this mixture was added 5 ml H ₂ 0 and then 20 ml CH ₂ C1 ₂ . The organic phase was extracted. To the residual inorganic phase was added again 20 ml CH ₂ CI ₂ and brine (ca. 10 ml). The organic phase was extracted. The combined organic phases afforded the crude product as a yellow liquid after solvent evaporation. The product was purified by column chromatography (9 >< 5 cm) on silica gel (Sigma, 230 - 400 mesh, 40 - 63 μ, average pore diameter 60 A, -120 g); eluent: hexane-ethyl acetate 7:3 (4 fractions were eluated) and then CH ₂ Cl ₂ -MeOH-NH ₃ 10: 1 :0.5 (this eluent dried over Na ₂ S0 ₄ overnight prior to use; two fractions were collected: desired product and then starting 9 in the end). Yield 861 mg (57%), yellow-dark oil. Elem. Anal : Calcd for C19H26N2S2 (346.55): C, 65.85; H, 7.56; N, 8.08%; Found: C, 65.77; H, 7.34; N, 8.05%. 1H NMR (400 MHz, CDC1 ₃ , 25 °C): δ 1.02 (m, 2H), 1.23 (m, 2H, NH), 1.73 (brs, 2Η), 1.93 (brs, 2Η), 2.03 (m, 1Η), 2.10-2.23 (m, 2Η), 2.27 (m, 1Η), 2.71 (m, 1Η), 2.96 (m, 1Η), 3.08 (t, ³ J _H - _H ~ 6 Hz, 2H), 3.90 (vd, ² J _H - _H ~ 14 Hz, 1H), 4.16 (vd, ² JH-H ~ 6 Hz, 1H), 6.95 (m, 2H), 7.20 (m, 2H), 7.29 (m, 2H), 7.38 (m, 2H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , 25 °C): δ 24.9 (s, 1C), 25.0 (s, 1C), 31.5 (s, 1C), 31.8 (s, 1C), 34.7 (s, 1C), 45.5 (s, 1C), 45.6 (s, 1C), 60.6 (s, 1C), 61.4 (s, 1C), 124.1 (s, 1C), 124.4 (s, 1C), 126.0 (s, 1C), 126.5 (s, 1C), 128.9 (s, 1C), 130.0 (s, 1C), 136.2 (s, 1C), 145.1 (s, 1C).

[0189] Example 4.3. Synthesis of ligand 12. To a stirred solution of (R,R)-OACH (1.53 g, 13.4 mmol, 98%> Aldrich) in 25 ml water containing 2.68 g NaOH (5 equiv, 67 mmol) was added dropwise (phenylthio)acetyl chloride (5 g, 26.8 mmol, 97%> Aldrich). The reaction mixture was stirred 3 h, the white precipitate was filtered, washed with water (2 x 15 ml, 2 x 50 ml), ethanol (2 x 10 ml), diethyl ether (3 ^x 15 ml) and dried under vacuum (jet pump, ~2 h) to afford 2.75 g (50 % yield) of product as a white solid. Elem. Anal: Calcd for C22H26N2O2S2 (414.58): C, 63.74; H, 6.32; N, 6.76%; Found: C, 63.42; H, 6.22; N, 6.59%. 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 1.12 (br m, 2H), 1.26 (br m, 2H), 1.68 (br m, 2H), 1.90 (d, J ~ 12 Hz, 2H), 3.25 (d, J ~ 17 Hz, 2H), 3.93 (d, J ~ 17 Hz, 2H), 3.63 (brs, 2H), 6.92 (brs, 2H), 7.13-7.45 (m, 10H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 24.5 (s, 2C), 32.0 (s, 2C), 37.1 (s, 2C), 53.6 (s, 2C), 126.5 (s, 2C), 128.1 (s, 4C), 129.2 (s, 4C), 135.0 (s, 2C), 168.4 (s, 2C).

[0190] Example 5. Synthesis of P(Q)NNS-type and PNNS -Type Chiral Ligands

[0191] Illustrative P(0)NNS-type and PNNS chiral ligands of Ci-symmetry are shown in Chart 5:

Chart 5.

13 13*

[0192] Air-stable ligand 13 was synthesized according to Scheme 7. The reaction was performed in air inside a fume hood. Ligand 13* may be prepared by reduction of 13 with a variety of reducing agents, includin silanes as shown in Scheme 7 (under argon).

10

13: y. 98%'

Scheme 7. Syntheses of P(0)NNS-type and PNNS chiral ligands of Ci-symmetry. °Crude yield.

[0193] Example 5.1. Synthesis of ligand 13^ A mixture of 10 (547 mg. 2.60 mmol) and diphenylvinylphosphine oxide (593 mg, 2.60 mmol) in 3 ml of water was refluxed for 24 h. The organic product was extracted with dichloromethane (3 >< 5 ml), dried over anhydrous MgSC^, followed by filtration, then concentrated to give yellow-red oily material (1 120 g, 98% crude yield). The oily material crystallizes as white powder upon passing through chromatography column (silicagel or alumogel) or upon standing to afford white-orange crystals. In the latter case, it was washed with Et ₂ 0 (3 x 15 ml), binary Et ₂ 0-pentane ( 1 : 1 , 25 ml each) and vacuum dried to afford white precipitate. Part of it was recrystallized from hexane-dichloromethane to afford a white crystalline material. Elem. Anal: Calcd for C ₂₅ H ₃₁ N ₂ OPS (438.57): C, 68.47; H, 7.12; N, 6.39%; Found: C, 68.49; H, 7.13; N, 6.30%. ³¹ P{1H} (162 MHz, CDC1 ₃ , r.t.): δ 31.0 (s). 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 0.83-1.07 (m, overlapped, 2H), 1.72 (br t, 2H), 1.68 (br t, 2H), 1.91 (brs, 2H), 2.00 (d, J~ 13 Hz, 1H), 2.05-2.24 (m, overlapped, 3H), 2.44-2.62 (m, 2H), 2.80 (vq, J~ 10 Hz, 1H), 3.06 (vq, J~ 10 Hz, 1H), 3.86 (d, J~ 14 Hz, 1H), 4.08 (d, J~ 14 Hz, 1H), 6.90 (s, 1H), 6.95 (vt, J~ 3 Hz, 1H), 7.19 (d, J~ 5 Hz, 1H), 7.40-7.56 (m, 6H), 7.69-7.84 (m, 4H). ¹³ C{1H} (100.5 MHz, CDCI ₃ , r.t.): δ 24.9 (two s, overlapped, 2C), 31.1 (d, J _C -p = 65 Hz, 1C), 31.5 (s, 1C), 40.0 (s, 1C), 45.5 (s, 1C), 53.5 (s, 1C), 60.5 (s, 1C), 61.5 (s, 1C), 124.1 (s, 1C), 124.4 (s, 1C), 126.6 (s, 1C), 128.7 (d, J _C - _P = 12 Hz, 4C _meta , Ph), 130.7 (d, J _C - _P = 9 Hz, AC _ortho , PPh ₃ ), 131.7 (d, Jc-P = 3 Hz, 2C _para , Ph), 133.0 (d, J _C _ _P = 99 Hz, 2C^ ₀ ), 145.1 (s, 1C).

[0194] Example 6. Preparation of Catalyst Complexes. Complexes of ruthenium, iridium, manganese, iron, cobalt, nickel or copper comprising the inventive ligands were prepared using the NNS-type, P(0)NS-type, PNS-type, SNNS-type, SNNP(0)-type, and SNNP- type poly dentate ligands and suitable precursors of transition metals under inert atmosphere. Synthesis of ruthenium(II) complexes of the general formula [RuCl ₂ (ligand)L] was typically performed by reacting the ligand with a suitable ruthenium precursor such as [RuCl ₂ (PPh ₃ )3], [RuCl ₂ (r| ⁴ -COD)] _n /L or [RuCl ₂ (DMSO) ₄ ] in a solvent at room temperature or reflux. Syntheses of iridium(I) or iridium(III) complexes were performed typically by reacting the ligand with a suitable iridium precursor such as [IrCl(r| ² -COE) ₂ ] ₂ in a solvent at room temperature. Synthesis of [MCl ₂ (ligand)] (M = Mn, Fe, Co, Cu) or [NiCl ₂ (ligand)(EtOH)] was performed typically by reacting the ligand with a suitable metal precursor such as MnCl ₂ , FeCl ₂ , CoCl ₂ , CuCl ₂ or NiCl ₂ in a solvent at room temperature.

[0195] Example 6.1. Synthesis and Characterization of Ruthenium Complexes Using NNS-Type Ligands. Chart 6 below illustrates Ruthenium Complexes of NNS-type ligands that were synthesized, isolated and subsequently used as precatalysts in catalytic reactions Chart 6.

B-1 C-1 C-2 C-3

[0196] Schemes 8 and 9 below illustrate several exemplary Ruthenium complexes of NNS-type ligands that were synthesized, isolated and subsequently used as precatalysts in catalytic reactions.

h, yield

F-1 : a/r- and moisture-siable

Scheme 9. Synthesis of complexes B-1, C-1, C-2, C-3 and chiral complex F-1. Isolated yields are shown. Stability refers to that in the solid-state.

[0197] Some suitable transition metal precursors useful for preparing embodiment complexes include, but are not limited to, [RuCl ₂ (PPh ₃ ) ₃ ], [RuCl ₂ (r| ⁴ -COD)]„/PR ₃ (COD = cyclo- octa-l,5-diene, PR ₃ = PPh ₃ , PCy ₃ ), [RuCl ₂ (r| ⁴ -COD)]„, [RuCl ₂ (DMSO) ₄ ] (DMSO =

dimethylsulfoxide) and [IrCl(r| ² -COE) ₂ ] ₂ (COE = cyclooctene).

[0198] Some embodiment complexes of Ruthenium were prepared by reacting a ligand selected from la, 2a, 3a, 4a, lb, 4b and 5a (in which E = morpholine) with either

[RuCl ₂ (PPh ₃ ) ₃ ] or [RuCl ₂ (r| ⁴ -COD)]„.

[0199] Example 6.1.1. Synthesis of Complex A-l. Method A. To [RuCl ₂ (PPh ₃ ) ₃ ] (360 mg, 0.375 mmol) was added a solution of la (100 mg, 0.375 mmol) in 5 ml of CH ₂ C1 ₂ with stirring. The resulting burgundy solution was stirred at room temperature. An analysis of the reaction mixture by ³¹ P NMR spectroscopy after 1 hour revealed complete conversion of the starting material into the product, indicated by a resonance at δ 40.9 ppm, and the presence of free PPh ₃ , δ -5.5 ppm). After reacting for a total of 2 hours, the burgundy solution was concentrated to approximately 40% of its original volume, followed by layering with diethyl ether (22 ml). After six days, the mother liquor was decanted, leaving a light pink powder. This powder was transferred to a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield of complex A-l : 236 mg (90%). Elem. Anal: Calc'd for

C3 ₂ H ₃₇ Ci ₂ N ₂ OPRuS (700.66): C, 54.86; H, 5.32; N, 4.00%. Found: C, 54.96; H, 5.19; N, 4.03%. ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 41.0 (s). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ 2.81 (vt, J~ 14 Hz, 1H), 2.93-3.07 (m, 2H), 3.16-3.39 (m, 7H), 3.46-3.58 (m, 2H), 3.62-3.68 (m, 3H), 3.81 (vt, J~ 13 Hz, 1H), 5.88 (brs, NH, 1Η), 6.98 (t, J~ 8 Hz, 2H), 7.20-7.33 (m, 12H), 7.72 (vt, J~ 9 Hz, 6H). ¹³ C{1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 44.9 (s, 1C), 47.0 (s, 1C), 48.4 (s, 1C), 52.9 (s, 1C), 54.7 (s, 1C), 59.3 (s, 1C), 60.2 (s, 1C), 61.6 (s, 1C), 127.1 (d, J _C - _P = 8.7 Hz, 6C _meta , Pi¾), 127.9 (s, 2C _meta , Ph), 128.5 (d, J _C - _P = 1.5 Hz, 3C _para , PPh ₃ ), 128.6 (s, \C _pam , Ph), 133.1 (s,

2C _ortho , Ph), 134.5 (d, Jc-P = 9.5 Hz, 6C _ortho , Pi¾), 134.8 (s, 1C^ ₀ , Ph), 137.7 (d, J= 36 Hz, ICipso); ³¹ P{1H} (162 MHz, CDC1 ₃ , r.t.): δ 40.3 (s). 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 2.74 (vt, J~ 14 Hz, 1H), 2.94-3.02 (m, 2H), 3.11-3.45 (m, 9H), 3.51-3.70 (m, 5H), 3.78 (vt, J~ 13 Hz, 1H), 5.87 (brs, NH, 1Η), 6.95 (t, J~ 8 Hz, 2H), 7.15-7.32 (m, 12H), 7.72 (t, J~ 9 Hz, 6H). ¹³ C{1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 45.2 (s, 1C), 47.2 (s, 1C), 48.5 (s, 1C), 52.8 (s, 1C), 54.8 (s, 1C), 58.9 (s, 1C), 60.2 (s, 1C), 61.6 (s, 1C), 127.3 (d, J _c _ _P = 8.7 Hz, 6C _meta , Pi¾), 128.1 (s, 2C _meta , Ph), 128.7 (d, Jc-P = 1.5 Hz, 3C _para , Pi¾), 128.8 (s, \C _para , Ph), 133.2 (s, 2C _ortho , Ph), 134.6 (d, Jc-P = 9.5 Hz, 6C _ortho , Pi¾), 134.5 (s, lC _ipso , Ph), 137.1 (d, J= 36 Hz, 3C _ipso ).

[0200] Example 6.1.2. Synthesis of Complex A-l. Method B. A mixture of

[RuCl ₂ (COD)] _n (359 mg, 1.281 mmol), PPh ₃ (336 mg, 1.281 mmol) and ligand la (341 mg, 1.281 mmol) was stirred in THF (15 ml) at 75 °C for 39 h in a KONTES® pressure tube. After cooling down, the resulting brick precipitate was collected on a filter frit, washed with diethyl ether (3 >< 5 ml) and vacuum dried. Recrystallization from hot dichloromethane following layering with diethyl ether afforded analytically pure complex A-l in 29% yield (260 mg).

[0201] Example 6.1.3. Synthesis of Complex A-2. Complex A-2 was prepared similarly to complex I Method A (vide supra) with the exception that ligand 2a was used instead of ligand la. After decantation of the mother liquor, the obtained red rhombic crystals were washed with diethyl ether (3 ^x 10 ml) and vacuum dried overnight. Isolated yield of complex A-2: 225 mg (75%) of CssHsgCbNzOPRuS- ICH2CI2 (based on 1H NMR. Elem. Anal: Calc'd for C ₃₃ H ₃₉ Cl ₂ N ₂ 0PRuS- lCH ₂ Cl ₂ (768.20): C, 51.07; H, 5.17; N, 3.50%. Found: C, 52.53; H, 5.38; N, 3.54%. The elemental analysis better fits the C ₃₃ H ₃₉ Cl ₂ N ₂ OPRuS 0.63CH ₂ Cl ₂ (768.20) formulation, Calc'd: C, 52.58; H, 5.28; N, 3.65%>. Some co-crystallized CH ₂ CI ₂ appears to have been lost during elemental analysis. Independent experiments showed that the amount of solvate depended on the drying time. The compound existed in CDC1 ₃ or CD ₂ C1 ₂ as a mixture of presumably two diastereomers (79:21 ratio). ³¹ P{ ¹ H} (162 MHz, CDC1 ₃ , r.t.): δ 39.6 (s, major, 79%), 40.3 (s, minor, 21%). ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 40.6 (s, major, 79%), 40.9 (s, minor, 21%).

[0202] Example 6.1.4. Synthesis of Complex A-3. Complex A-3 was prepared similarly to complex I, following method A {vide supra) with the exception that ligand 3a was used instead of ligand la. After decantation of the mother liquor, the obtained red crystals were washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield: 209 mg (87%). Elem. Anal: Calc'd for C ₂ 7H ₃₅ Cl ₂ N ₂ OPRuS (638.59): C, 50.78; H, 5.52; N, 4.39%.

Found: C, 50.77; H, 5.51; N, 4.29%. The compound exists in CD ₂ CI ₂ as a mixture of presumably two diastereomers (74:26 ratio). ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 40.9 (s, minor, 24%), 41.9 (s, major, 76%).

[0203] Example 6.1.5. Synthesis of Complex A-6. Complex A-6 was prepared similarly to complex A-l, method A (vide supra) with the exception that ligand 4a was used instead of ligand la. After decantation of the mother liquor, a large (> 1 cm) red crystal was transferred onto a filter frit , washed with diethyl ether (3 ^x 10 ml), dried under vacuum, broken and vacuum dried overnight. Isolated yield: 238 mg (87%). Elem. Anal: Calc'd for

C ₃₄ H ₄ iCl ₂ N ₂ OPRuS (728.72): C, 56.04; H, 5.67; N, 3.84%. Found (under nitrogen): C, 56.32; H, 5.75; N, 3.85%). The compound exists in CD ₂ CI ₂ as a mixture of presumably two diastereomers (99: 1 ratio). ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 42.9 (s, minor, 1%), 46.0 (s, major, 99%). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t., major): δ 2.03 (d, J~ 13 Hz, 1H), 2.17 (t, J~ 13 Hz, 1H), 2.25 (q, J~ 13 Hz, 1H), 2.25 (d, J~ 14 Hz, 2H), 2.92-3.23 (overlapped m, 1 OH), 3.52 (d, J~ 19 Hz, 1H), 3.58-3.83 (overlapped m, 4H), 4.78 (brs, 1H, NH), 6.87 (brs, 2Η), 7.20 (brs, 3Η), 7.39 (brs, 9Η), 7.93 (brs, 6Η). ¹³ C{1H} (100.5 MHz, CD ₂ C1 ₂ , r.t., major): δ 24.4 (s, 1C), 25.2 (s, 1C), 37.2 (s, 1C), 49.6 (s, 1C), 50.1 (s, 1C), 51.5 (s, 1C), 51.7 (s, 1C), 58.0 (s, 1C), 60.1 (s, 1C), 61.2 (s, 1C), 127.0 (s, \C _para , Ph), 127.2 (d, J _C _ _P = 9 Hz, 6C _meta , Pi¾), 128.3 (s, 2C _meta , Ph), 128.7 (brs, Cpara, VPfo), 129.2 (s, 2C _ort ho, Ph), 135.2 (d, J _C - _P = 9 Hz, 6C _ortAo , ?Ph ₃ ), 136.6 (s, 1C^ ₀ , Ph), 136.9 (d, J= 36 Hz, 3C^ ₀ ).

[0204] Complexes A-1, A-2, A-3, and A-6 were air-stable and moisture stable. After they were prepared, they were all handled in air, and all were characterized by elemental analysis and NMR (1H, ¹³ C, ³¹ P) spectroscopy (vide supra). In addition, X-Ray crystal structures of complexes A-1, A-2, A-3, and A-6 were obtained, and shown to be isostructural K ³ [NN',S]- tridentate tra/75-[Ru ⁿ Cl ₂ {K ³ (N,N',5)-]S[NS-type ligand} (PPh ₃ )] complexes.

[0205] It may also be worth making some comparisons about the solution phase behavior of complexes A-1, A-2, A-3, and A-6. A second isomer (presumably diastereomer) was not detected for complex A-1 in CD ₂ C1 ₂ by NMR spectroscopy at ambient temperature. For complexes A-2 and A-3, the quantity of a second isomer slightly increases with a decrease in bulkiness of the substituent on the sulfur donor atom (21% for A-2 and 24% for A-3. For complex A-1, which is a 5,6-metallacycle, the second isomer was present at only 1% of the total amount (compared to 21% for complex II, a 5,5-metallacycle). The X-ray structures of these complexes resembled one another other, being 5,5 or 5,6-ruthenacycles in which the three heteroatoms (N, N and S) are located in a single plane. The chlorine atoms are located in trans- orientation to each other, and the PPh ₃ moiety is located trans to the NH group. These structures resemble those for known Ru-PNN complexes and for other pincer Ru complexes that include P/N tridentate ligands. Upon dissolution of X-Ray quality crystals of A-1, A-2, A-3, and A-6, two isomers (presumably diastereomers) were observed in their respective solution NMR spectra.

[0206] Example 6.1.6. Synthesis of Complex J-l. Complex J-l was prepared similarly to complex A-1 following method A with the exception that ligand lb was used instead of ligand la. ³¹ P NMR analysis of the reaction mixture in 1 h revealed full conversion of the starting material into presumably cz5-[Ru(PPh ₃ ) ₂ Cl ₂ (A ,5'-ligand)], δ 26.8 ppm (brs, IP), 36.7 ppm (d, ² Jp_p = 31 Hz, IP), and free PPh ₃ , δ -5.5 ppm. The air-sensitive mixture was stirred for 2 hours and then concentrated to approximately 40% of the original volume, and then layered with diethyl ether (22 ml) and left for eight days. After decantation of the mother liquor, the obtained red needle crystals were transferred onto a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield: 162 mg (60%). Elem. Anal. : Calc'd for

C ₆₆ H ₇₈ Cl ₄ N ₄ 0 ₂ P ₂ Ru ₂ S ₂ (1429.38): C, 55.46; H, 5.50; N, 3.92%. Found: C, 55.68; H, 5.49; N, 3.79%. The compound is air-stable at least in the solid-state. The obtained needle-like crystals were sparingly soluble in CD ₂ C1 ₂ , CDC1 ₃ , CD ₃ OD, acetone-^ and DMF- y. Saturated solutions of small concentrations exhibited complicated ³¹ P NMR spectra.

[0207] Example 6.1.7. Synthesis of Complex J-2. Complex J-2 was prepared similarly to complex J-1 with the exception that ligand 4b was used instead of ligand lb. After decantation of the mother liquor, the resulting orange solid was transferred to a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield: 134 mg (48%), orange solid. Elem. Anal: Calc'd for C ₇ oH ₈₆ Cl ₄ N ₄ 0 ₂ P ₂ Ru ₂ S ₂ (1485.49): C, 56.60; H, 5.84; N, 3.77%. Found: C, 56.42; H, 5.85; N, 3.73%. Similarly to J-1, dimeric J-2 is sparingly soluble in CD ₂ C1 ₂ , CDCI ₃ , CD ₃ OD, acetone-^ and DMF- y. Upon standing, the mother liquor produced red crystals after about 1 week (not quantified). The X-Ray structural analysis identified the product as an unsymmetrical, trichloro-bridged bimetallic complex containing a K ² [N',5 -bidentate ligand, [Ru{K ² (N S)-4b}(PPh ₃ )^-Cl) ₃ RuCl(PPh ₃ ) ₂ ] (J-3). This could formally be viewed as the product of an association reaction involving a 16 electron monomer of J-2, (i.e. complex [RuCl ₂ {K ² (N',5)-4b}(PPh ₃ )]) and a 14 electron unsaturated fragment, [RuCl ₂ (PPh ₃ ) ₂ ], that intercept each other within the reaction mixture. Thus this product is an intermediate or a byproduct formed as a result of this complicated reaction. Similarly to J-1, the compound J-2 is sparingly soluble in CD ₂ C1 ₂ , CDC1 ₃ , CD ₃ OD, acetone -d ₆ and DMF- y. Saturated solutions (low concentrations) exhibit complicated ³¹ P { ¹ H} NMR spectra.

crystallization Et ₂ 0/CH ₂ CI ₂

4b

[RuCI ₂ (PPh ₃ ) ₃ ] complicated ^J1 P NMR (1-6 h)

CH ₂ CI ₂ r.t., 2 h

J -2 J -3

isolated (48 % y., orange solid) red crystals from mother liquor

(produced after ~1 week)

[0208] The identity of embodiment complexes J-l and J-2 was supported by elemental analysis, and the mode of ligand coordination in J-l was determined from single-crystal X-Ray structural analysis. Such crystallographic data show that ligand lb binds to each Ru atom in a bidentate K ² [N',5 -fashion, affording a five-membered NS ring. The morpholine moieties are directed away from the metal centers. The Ru atoms are connected via two bridging chlorine (CI) atoms. Each terminal CI atom is believed to participate in hydrogen bonding with the NH group of the ligand coordinated to the other Ru atom. It may be worth noting that compared to the formation of complexes using ligands la, 2a, and 3a, in situ ³¹ P NMR spectroscopic monitoring of the reactions with ligands lb and 4b in CD ₂ CI ₂ solvent indicated more complicated mixtures prior to crystallization.

[0209] Example 6.1.8. Synthesis of Complex L-l. Complex L-l was prepared similarly to complex A-1 following method A with the exception that ligand 5 a was used instead of ligand la. The in situ ³¹ P NMR monitoring of the reaction of ligand 5a with [RuCl ₂ (PPh ₃ ) ₃ ] revealed a complicated reaction mixture (in a separate experiment, the composition remained unchanged after 5 h). In 2 hours the solution was concentrated to approximately 40% of the original volume and was then layered with diethyl ether (22 ml). After 20 days, the mother liquor was decanted and the resulting scarlet powder was transferred to a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield: 201 mg (81%). Elem. Anal.: Calc'd for C ₅ 8H ₆₆ Cl4N40 ₂ P2Ru2S2 (1321.20): C, 52.73; H, 5.04; N, 4.24%. Found: C, 51.70; H, 4.85; N, 4.24%. 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t., major): δ 1.42 (d, J~ 14 Hz, 1H), 1.84 (dd, J~ 5 Hz, J ~ 14 Hz, 1H), 2.16 (t, J~ 14 Hz, 1H), 2.47 (d, J~ 13 Hz, 1H), 2.63 (d, J~ 16 Hz, 1H), 2.85 (brs, 1H), 3.28 (d, J~ 13 Hz, 1H), 3.45 (d, J~ 13 Hz, 1H), 3.54-3.79 (overlapped m, 4H), 3.84-4.06 (overlapped, 2H), 4.29 (dt, J~ 3 Hz, J~ 14 Hz, 1H), 6.87 (brs, 1H), 7.02 (m, 1H), 7.39 (brs, 10H), 7.83 (d, J~ 5 Hz, 2H), 8.07 (brs, 5H). The NMR (1H, ³¹ P) spectroscopic analysis and elemental analysis are consistent with the formula shown for complex L-1. Complex L-1 is air- stable at least in the solid-state. It is sparingly soluble in CD ₂ CI ₂ , CDCI ₃ and almost insoluble in THF-dg, MeOD and acetone-^. These solutions were air-sensitive. It should be noted that if the scarlet precipitated powder was collected after 10 days, the yield dropped to 14%>. An X-ray structure of some red crystals produced from the mother liquor of L-1 was obtained; this X-Ray structure of these red crystal reveals an ion-pair complex [Ru ₂ ^ ₂ -Cl) ₃ Cl ₂ (PPh ₃ ) ₄ ] ^~ 5aH ⁺ (L-2), which consists of a binuclear trichloro-bridged anion [Ru ₂ ^ ₂ -Cl) ₃ Cl ₂ (PPh ₃ ) ₄ ] ^~ and protonated

5a.

[RuCI ₂ (PPh ₃ ) ₃ ] +

L-1 L-2

isolated (81 % y., scarlet) crystals from mother liquor [0210] Example 6.1.9. Synthesis of Complex B-l. The procedure for preparing complex B-l was similar to that for preparing complex A-l, method A, with the exception that ligand lc was used instead of ligand la. After the decantation of the mother liquor, the obtained light pink precipitate was collected on a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight. Isolated yield: 218 mg (85%). Elem. Anal.: Calc'd for

C ₃₂ H ₃₇ CI ₂ N ₂ PRUS (684.67): C, 56.14; H, 5.45; N, 4.09%. Found: C, 56.33; H, 5.36; N, 3.79%. ³¹ P{1H} (162 MHz, CDCI ₃ , r.t.): δ 42.2 (s). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ 1.15 (vq, J~ 8 Hz, 1H), 1.35 (vq, J~ 8 Hz, 1H), 1.60 (m, 2H), 2.41 (vq, J~ 12 Hz, 1H), 2.53 (d, J~ 12 Hz, 1H), 2.93 (t, J~ 13 Hz, 1H), 3.05 (m, 3H), 3.15 (d, J~ 9 Hz, 1H), 3.29 (d, J~ 9 Hz, 1H), 3.39 (d, J~ 11 Hz, 1H), 3.56 (m, 2H), 3.15 (vq, J~ 11 Hz, 1H), 5.85 (brs, NH, 1Η), 6.94 (t, J~ 8 Hz, 2H), 7.14 (t, J~ 7 Hz, 1H), 7.14-7.25 (m overlapped, 6H), 7.26-7.33 (d, J~ 8 Hz, 6H), 7.66 (t, J ~ 9 Hz, 5H). ¹³ C{1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 20.5 (s, 1C), 22.1 (s, 1C), 45.4 (s, 1C), 47.3 (s, 1C), 49.3 (s, 1C), 57.7 (s, 1C), 61.2 (s, 1C), 62.5 (s, 1C), 127.0 (d, J _C - _P ~ 8 Hz, 6C _meta , Pi¾),

128.0 (s, 2C _meta , Ph), 128.4 (d, J _C - _P ~ 1.5 Hz, 3C _para , PPh ₃ ), 128.5 (s, lC^ _ra , Ph), 133.0 (s, 2C _ortho , Ph), 134.6 (d, Jc-P ~ 9 Hz, 6C _ortho , PPh ₃ ), 135.0 (s, lC _ipso , Ph), 137.2 (d, J= 36 Hz,

3 Cipso ■

[0211] Example 6.1.10. Synthesis of Complex C-1. Complex C-1 was prepared similarly to complex A-l with the exception that ligand Id was used instead of ligand la.

Layering with diethyl ether afforded burgundy colored crystals that were collected on a filter frit, washed with Et ₂ 0 (3 ^x 10 ml) and vacuum dried overnight. The elemental analysis, NMR and X- Ray crystallography reveals complex C-1 exists as a dichloromethane solvate. Isolated yield: 218 mg (78%). Elem. Anal: Calc'd for C3oH ₃₅ Cl ₂ N ₂ PRuS lCH ₂ Cl ₂ (743.55): C, 50.08; H, 5.02; N, 3.77%; Found C, 50.33; H, 5.12; N, 3.93%. ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 44.3 (s). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t): δ 2.20 (d, J~ 12 Hz, 1H), 2.35 (s, 3H), 2.48 (s, 3H), 3.05 (vd, J~ 12 Hz, 1H), 3.17-3.26 (m, 1H), 3.26-3.35 (m, 2H), 3.43 (d, J~ 11 Hz, 1H), 3.59 (m, 2H), 5.37 (CH ₂ C1 ₂ ), 5.88 (brs, NH, 1Η), 6.99 (t, J~ 8 Hz, 2H), 7.19-7.26 (m, 6H), 7.26-7.35 (m, 6H), 7.69 (t, J~ 9 Hz, 6H). ¹³ C {1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 44.9 (s, 1C), 47.1 (s, 1C), 48.5 (s, 1C), 51.2 (s, 1C), 49.3 (s, 1C), 52.8 (s, 1C), 53.8 (S, 1C, CH ₂ C1 ₂ ), 67.0 (s, 1C), 127.1 (d, J _C - _P ~ 8 Hz, 6C _meta , PPh), 127.9 (s, 2C _meta , Ph), 128.4 (d, J _C - _P ~ 1.5 Hz, 3C _para , PPh ₃ ), 128.6 (s, \C _para , Ph),

133.1 (s, 2C _ortho , Ph), 134.3 (d, J _C - _P ~ 9 Hz, 6C _ortho , Pi¾), 135.2 (s, lC _ipso , Ph), 138.0 (d, J~ 37 Hz, 3C ip _SO . [0212] Complex C-l was also prepared using [RuCl ₂ (COD)] _n as a precursor. Thus, a mixture of [RuCl ₂ (COD)] _n (309 mg, 1.103 mmol), PPh ₃ (289 mg, 1.103 mmol) and ligand Id (248 mg, 1.103 mmol) was stirred in toluene (10 ml) at 115°C for 24 h in a KONTES® pressure tube. After cooling, the resulting brick colored precipitate was filtered on a filter frit, washed with diethyl ether (3 x 10 ml) and vacuum dried to afford 494 mg of a light pink crude material (Found C, 53.43; H, 5.26; N, 4.08%). Recrystallization from hot THF, filtering and layering with diethyl ether, afforded burgundy crystals (261 mg, 32% yield as a THF solvate). Based on NMR analysis, these crystals represent a THF solvate of complex C-l. The crystals were found to lose solvent based on elemental analysis. Elem. Anal: Calc'd for C ₃ oH ₃₅ Cl ₂ N ₂ PRuS (658.63): C, 54.71; H, 5.36; N, 4.25%; Found C, 54.37; H, 5.66; N, 3.87%.

[0213] X-ray structures were obtained for both complex B-l and complex C-l. The complexes B-l and C-l are isostructural; their solid state structures are also similar to those of octahedral complexes A-1, A-2, A-3, and A-6. The solution behavior of complexes B-l and C-l was similar to that of complex A-1 in that no detectable amount of a second isomer was observed in solution. Complexes B-l and C-l were tested as pre-catalysts for hydrogenation.

[0214] Example 6.1.11. Synthesis of Complex A-4. A mixture of [RuCl ₂ (COD)] _n (309 mg, 1.103 mmol), PCy ₃ (309 mg, 1.103 mmol) and la (294 mg, 1.103 mmol) was stirred in toluene (10 ml) at 115 °C for 48 h in a KONTES® pressure tube. After cooling down, the brick colored precipitate was collected on a filter frit, washed with Et ₂ 0 (3 x 10 ml) and vacuum dried to afford 642 mg of the crude material. To the crude material was added CH ₂ C1 ₂ (~ 32 ml) and the obtained mixture was brought to reflux and filtered using a Whatman syringe filter (PTFE membrane, pore size 0.45 μιη). Layering the obtained red-brown solution with Et ₂ 0 (125 ml) afforded 327 mg (41%) of the product as a pink-brown powder after 5 days. Elem. Anal.: Calcd for C ₃₂ H ₅₅ Cl ₂ N ₂ OPRuS (718.81): C, 53.47; H, 7.71; N, 3.90%. Found: C, 53.11; H, 8.00; N, 3.86%. ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 24.0 (s). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ 0.09 (brs, 1H), 0.92 (brs, 2H), 1.04-1.63 (m, 15H), 1.63-2.05 (m, 9H), 2.10-2.45 (brs, 3H), 2.45-2.70 (brs, 1H), 2.83-3.28 (overlapped, 7H), 3.31-3.56 (overlapped, 6H), 3.56-3.90 (overlapped, 4H), 3.98 (t, J~ 8 Hz, 1H), 5.57 (brs, NH, 1H), 7.31 (t, J~ 7 Hz, 2H), 7.38 (t, J~ 6 Hz, 1H), 8.15 (d, J~ 7 Hz, 2H). ¹³ C{1H} selected for the coordinated NNS ligand (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 46.6 (s, 1C), 46.8 (s, 1C), 48.3 (s, 1C), 53.9 (s, 1C, overlapped with CD ₂ C1 ₂ peak), 54.8 (s, 1C), 60.0 (s, 1C), 60.7 (s, 1C), 61.7 (s, 1C), 128.1 (s, 2C _meta , Ph), 129.3 (s, \C _pam , Ph), 134.9 (s, 2C _ortho , Ph), 138.0 (s, \C _ipso , Ph).

[0215] Example 6.1.12. Synthesis of Complex K-1. A mixture of [RuCl ₂ (COD)] _n (155 mg, 0.552 mmol) and la (147 mg, 0.552 mmol) was stirred in toluene (10 ml) at 115 °C for 48 h in Kontes pressure tube. After cooling, a brick-colored precipitate was collected on a filter frit, washed with Et ₂ 0 (3 x 10 ml) and vacuum dried on the filter. The material was extracted on the filter with 5 ^x 3 ml CH ₂ C1 ₂ allowing the filtrates to be collected in 5 separate vials. A red solution in each vial was layered with Et ₂ 0 (20 ml). In 1 week, the combined precipitates (or red crystals) from each vial were collected, washed with Et ₂ 0 (3 x 10 ml) and vacuum-dried to afford 144 mg of the desired product (60%). Elem. Anal: Calcd for C28H44CI4N4O2RU2S2 (876.75): C, 38.36; H, 5.06; N, 6.39%. Found C, 38.38; H, 4.99; N, 6.32%. Elem. Anal: Calcd for C28H44CI4N4O2RU2S2 (876.75): C, 38.36; H, 5.06; N, 6.39%. Found (under nitrogen): C, 38.61; H, 4.99; N, 6.17%. The complex is poorly soluble in CDC1 ₃ , slightly better in CD ₂ C1 ₂ . 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t., saturated): δ 2.00 (brs, 1H), 2.15 (d, J~ 14 Hz, 1H), 2.37 (t, J~ 12 Hz, 1H), 2.15 (m, 4H), 2.75-2.94 (m, 3H), 3.04 (d, J~ 14 Hz, 1H), 3.07-3.23 (m, 5H), 3.38 (m, 2H), 3.44-3.62 (m, 3H), 3.61-3.75 (m, 3H), 3.79 (d, J~ 12 Hz, 1H), 3.87 (t, J~ 14 Hz, 1H), 3.93-4.09 (overlapped m, 3H), 4.06 (brs, 1H), 4.44 (t, J~ 11 Hz, 1H), 4.72 (brs, 1H, possibly NH), 5.07 (d, J~ 18 Hz, 1H), 6.72-8.85 (overlapped, 10H), 9.19 (brs, 1H, NH - C1). The same compound is obtained if the synthesis is carried out in the presence of P(C ₆ F ₅ ) ₃ .

[0216] An X-ray structure of complex K-1 revealed that one ligand coordinates to one Ru atom via mer-fashion. A second ligand coordinates to second Ru atom via ^ac-fashion. Both Ru atoms are connected via one bridging CI atom. One S(Ph) atom is part of mer-coordinated la. There appears to be a hydrogen-bonding interaction between one NH group of the fac- coordinated ligand and terminal CI atom attached to the first Ru atom. Complex K-1 exists as a single species in solution. The NH hydrogen atom H-bonded to the chloride ligand appears at δ 9.19 ppm in the 1H NMR spectrum. It is shifted to low field by Δδ = 4.47 ppm relative to the NH resonance of the non-H bonded NH group.

[0217] Example 6.1.13. Synthesis of Complex A-5. A mixture of [RuCl ₂ (DMSO) ₄ ] (190 mg, 0.392 mmol) and ligand la (105 mg, 0.392 mmol) was stirred in toluene (5 ml) at 115 °C for 24 h in a KONTES® pressure tube. After cooling, the red precipitate was collected on a filter frit, washed with Et ₂ 0 (3 x 10 ml) and vacuum dried to afford 116 mg of crude material. The material was dissolved in CH ₂ CI ₂ (3 ml), filtered via a Whatman syringe filter (PTFE membrane, pore size 0.45 μιη) and layered with Et ₂ 0 (~20 ml). A red crystalline solid was obtained in 41% yield (84 mg). Elem. Anal: Calcd for C ₁₆ H ₂₈ CI ₂ N ₂ O ₂ RUS ₂ (516.50): C, 37.21; H, 5.46; N, 5.42%. Found: C, 37.37; H, 5.41; N, 5.25%. 1H NMR for major diastereomer (400 MHz, CD ₂ CI ₂ , r.t.): δ 2.81 (s, 3H), 2.91 (t, J~ 13 Hz, 1H), 3.11 (m, 1H), 3.24 (s, 3H), 3.29-3.74 (m, 11H), 3.79 (t, J~ 12 Hz, 1H), 3.93 (t, J~ 13 Hz, 1H), 4.05 (t, J~ 13 Hz, 1H), 5.40 (brs, NH, 1H), 7.37 (t, J~ 7 Hz, 2H), 7.46 (t, J~ 6 Hz, 1H), 7.98 (d, J~ 7 Hz, 2H). ¹³ C{1H} for major diastereomer (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 45.0 (s, 1C), 47.5 (s, 1C), 47.6 (s, 1C), 48.3 (s, 1C), 49.1 (s, 1C), 54.0 (s, 1C, overlapped with CD ₂ C1 ₂ peak), 55.4 (s, 1C), 58.4 (s, 1C), 60.7 (s, 1C, CH ₃ ), 61.7 (s, 1C, CH ₃ ), 128.9 (s, 2C _meta , Ph), 130.1 (s, lC^ _ra , Ph), 133.3 (s, 2C _ortho , Ph), 133.6 (s, \C _ipso , Ph).

[0218] The X-Ray structure of A-5 showed a solid state structure that is similar to the structures of complexes A-1, A-2, A-3, and A-6. Complex A-5 crystallized as four independent diastereomers whose asymmetric centers originate from the N-nitrogen and sulfur atoms, respectively. In solution, one of the diastereomers was preferred relative to the others present (approximately 90% level).

[0219] Example 6.1.14. Synthesis of Complex C-2. A mixture of [RuCl ₂ (COD)] _n (309 mg, 1.103 mmol), PCy ₃ (309 mg, 1.103 mmol) and Id (248 mg, 1.103 mmol) was stirred in toluene (10 ml) at 115 °C for 48 h (in a KONTES® pressure tube). After cooling, the brick colored precipitate was filtered on a filter frit, washed with Et ₂ 0 (3 x 10 ml) and partially vacuum dried on the filter (vacuum pump). The residue was extracted from the filter frit with dichloromethane (6 >< 3 ml). The obtained solution was layered with Et ₂ 0 (100 ml). Red-brown crystals were collected in few days (521 mg, 70%> yield). Elem. Anal: Calcd for

C ₃₀ H ₅₃ Cl ₂ N ₂ PRuS (676.77): C, 53.24; H, 7.89; N, 4.14%. Found: C, 53.10; H, 7.95; N, 4.05%. ³¹ P{1H} (162 MHz, CDC1 ₃ , r.t.): δ 27.0 (s). 1H NMR (400 MHz, CDC1 ₃ , r.t.): δ 0.78-3.90 (overlapped m, 47H), 5.57 (brs, 1H, NH), 7.22-7.53 (m, 3Η), 8.10-8.30 (m, 2Η). ¹³ C{1H} (100.5 MHz, CDC1 ₃ , r.t., selected without PCy ₃ carbon atoms): δ 46.7 (s, 1C), 46.8 (s, 1C), 48.5 (s, 1C), 52.3 (s, 1C), 54.2 (s, 1C), 67.2 (s, 1C), 128.2 (s, 2C _meta , Ph), 129.4 (s, \C _para , Ph), 134.9 (s, 2C _ortho , Ph), 137.8 (s, \C _ipso , Ph).

[0220] Example 6.1.15. Synthesis of Complex C-3. Prepared similarly as Complex C- 2, using ligand 2d. The compound exists in CDC1 ₃ as a mixture of presumably two diastereomers (79:21 ratio). ³¹ P{1H} (162 MHz, CDC1 ₃ , r.t.): δ 28.8 (s, minor, 21%), 29.0 (s, major, 79%). 1H NMR (400 MHz, CDC1 ₃ , r.t., selected): δ 2.09 (CH ₃ , major), 2.59 (CH ₃ , major), 2.83 (CH ₃ , major), 4.80 (vt, NH minor), 5.09 (vt, NH major). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t., selected without PCy ₃ carbon atoms, major): δ 20.9 (s, 1C), 43.3 (s, 1C), 46.6 (s, 1C), 48.1 (s, 1C), 52.0 (s, 1C), 55.1 (s, 1C), 67.2 (s, 1C).

[0221] Example 6.1.16. Synthesis of Complex F-l. To [RuCl ₂ (PPh ₃ ) ₃ ] (556 mg, 0.58 mmol) was added a solution of ligand 11 (201 mg, 0.58 mmol) in 7 ml of CH ₂ C1 ₂ with stirring. The resulting burgundy solution was stirred at r.t. for 2 hrs and evaporated. Diethyl ether was added to cause precipitation. The light-brown precipitate was collected on frit filter and washed with Et ₂ 0 (3 x 10 ml), vacuum dried and recrystallized from dichloromethane/Et ₂ 0. Elem.

Anal: Calcd for C ₃₇ H ₄ iCl ₂ N ₂ PRuS ₂ (780.81): C, 56.91; H, 5.29; N, 3.59%. Found: C, 57.41; H, 5.52; N, 3.56%). In alternative procedure, [RuCl ₂ (PPh ₃ ) ₃ ] (310 mg, 0.32 mmol) and ligand 11 (112 mg, 0.32 mmol) were refluxed in 2 ml of toluene with stirring. The product was separated from PPh ₃ excess on alumogel column (A1 ₂ 0 ₃ neutral, hexane-ethyl acetate 7:3, R _f = 0.4, air). ³¹ P{1H} (162 MHz, CD ₂ C1 ₂ , r.t.): δ 48.5 (s). 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ 0.88-1.84 (overlapped, 3H), 1.21-1.45 (overlapped, 3H), 1.72 (d, J~ 11 Hz, 1H), 2.58 (d, J~ 11 Hz, 1H), 2.77 (m, 1H), 3.08-3.26 (overlapped m, 2H), 3.45-3.74 (overlapped m, 3H), 3.92 (vt, J~ 10 Hz, 1H), 4.34 (d, J~ 15 Hz, 1H), 4.49 (vt, J~ 10 Hz, 1H), 5.41 (brs, 1H, NH), 6.60 (s, 1Η), 6.86 (s, 1Η), 7.01 (s, 2Η), 7.16-7.28 (m, 11Η), 7.42 (d, J~ 15 Hz, 2H), 7.46-7.62 (m, 6H). ¹³ C{1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.,): δ 24.2 (s, 1C), 25.6 (s, 1C), 32.0 (s, 1C), 34.7 (s, 1C), 44.9 (s, 1C), 45.9 (s, 1C), 52.9 (s, 1C), 63.2 (s, 1C), 71.4 (s, 1C), 125.8 (s, 1C), 126.8 (s, 1C), 127.1 (s, 1C),

127.7 (d, Jc-P = 9 Hz, 6C _meta , Pi¾), 128.2 (s, 2C _meta , Ph), 128.7 (d, J _C - _P = 1.5 Hz, 3C _para , PPh ₃ ),

128.8 (s, lC _para , Ph), 133.3 (s, 2C _ortho , Ph), 133.9 (d, J _C _ _P = 10 Hz, 6C _ortho , Pi¾), 135.2 (s, lC _ipso , Ph), 137.1 (d, J= 36 Hz, 3C^ ₀ ), 142.9 (s, 1C).

[0222] Example 6.2. Synthesis and Characterization of Ruthenium Complexes Using P(0)NS-Type Ligands .

[0223] Scheme 10 below illustrates Ruthenium Complexes of P(0)NS-type ligands that were synthesized, isolated and subsequently used as precatalysts in catalytic reactions.

Scheme 10

[0224] Example 6.2.1. Synthesis of Complex D-1. To [RuCl ₂ (PPh ₃ ) ₃ ] (420 mg, 0.438 mmol) was added a solution of crude ligand 8 (140 mg, 0.438 mmol) in 6 ml of CH ₂ C1 ₂ with stirring. The resulting burgundy solution was stirred at r.t. for 90 min ( ³¹ P NMR analysis of the reaction mixture performed after 1 h (CDC1 ₃ ) reveals full conversion of the starting material into the product (represented by two -1 : 1 isomers: 5 43.9 (s, PPh ₃ , 24%), 45.1 (s, PPh ₃ , 26%), 52.7 (s, P(0)Ph ₂ , 24%), 52.8 (s, P(0)Ph ₂ , 26%)) and free PPh ₃ (δ -5.5 ppm)) and then concentrated to ~ 40% in volume. The solution was layered with Et ₂ 0 (22 ml) and left for six days. After decantation of the mother liquor, the obtained brick-colored precipitate was transferred to a filter frit, washed with Et ₂ 0 (3 x 10 ml) and vacuum dried overnight. Isolated yield: 266 mg (81 >). Elem. Anal. (%): Calc. C, 55.78; H, 4.95; N, 1.86; Fnd C, 55.62; H, 4.94; N, 1.90. The compound crystallizes from dichloromethane-diethyl ether as a single isomer having four atoms P(0)NS located in one plane, based on X-Ray single crystal analysis. Upon dissolution, two isomers, possibly diastereomers, are observed within the mixing time. ³¹ P{ ¹ H} NMR

spectroscopy of the isomeric mixture (162 MHz, CD ₂ C1 ₂ , 25 °C): δ 44.2 (s, PPh ₃ , 24%), 45.4 (s, PPh ₃ , 26%), 52.3 (s, P(0)Ph ₂ , 24%), 53.4 (s, P(0)Ph ₂ , 26%). 1H NMR of the isomeric mixture (400 MHz, CD ₂ C1 ₂ , 25 °C): δ 1.22 (s, 3.21 H, SMe), 1.24 (s, 3.00 H, SMe), 2.13 (dt, J~ 13 Hz, J ~ 4 Hz, 1.00 H), 2.27 (d, J~ 14 Hz, 1.00 H), 2.56 (dt, J~ 13 Hz, J~ 4 Hz, 1.07 H), 2.73-2.99 (m, 5.21 H), 3.17 (brt, 2.16 H), 2.24-2.42 (m, 4.21 H), 3.96 (q, J~ 13 Hz, 1.00 H), 4.17 (q, J~ 13 Hz, 1.07 H), 4.87 (vt, J~ 11 Hz, 1.07 H), 5.13 (vt, J~ 11 Hz, 1.00 H), 7.25-7.94 (m, 51.75 H, Ph). Selected ¹³ C{1H} NMR (only sp ³ carbon atoms) of the major isomer (100.5 MHz, CD ₂ C1 ₂ , 25 °C): δ 16.1 (s, 1C), 29.8 (d, J _C - _P ~ 68 Hz, 1C), 38.7 (s, 1C), 44.3 (d, J _C - _P ~ 6 Hz, 1C), 49.3 (s, 1C). Selected ¹³ C {1H} NMR (only sp ³ carbon atoms) of the minor isomer (100.5 MHz, CD ₂ C1 ₂ , 25 °C): δ 19.0 (s, 1C), 29.5 (d, J _C - _P ~ 67 Hz, 1C), 37.3 (s, 1C), 44.0 (d, J _C - _P ~ 6 Hz, 1C), 50.7 (s, 1C). [0225] Example 7. Synthesis and Characterization of Iridium Complexes Using NNS-Type Ligands

[0226] Chart 7 below illustrates Iridium Complexes of NNS-type ligands that were synthesized, isolated and subsequently used as precatalysts in catalytic reactions.

Chart 7

N- - N-4

N-5 N-1

[0227] Complexes M-1 and N-1 to N-5 were synthesized according to Scheme 11.

[0228] In general, the inventive complexes of iridium were prepared by reacting a ligand with a suitable iridium-containing precursor in a suitable solvent.

[0229] Ligands la, 2a, 4a, and 4b were reacted with [IrCl(r| ² -COE) ₂ ] ₂ in THF

(tetrahydrofuran) solvent at room temperature. The outcome of these reactions depended on the nature of the Ri group attached to the S donor atom. Ligands 6 and 7 were reacted with [IrCl(Y| ² - COE) ₂ ] ₂ in binary toluene-MeCN solvent at room temperature.

[0230] Reaction of ligand la with [IrCl(r| ² -COE) ₂ ] ₂ in THF solvent at room temperature afforded the yellow, slightly oxygen-sensitive complex [Ir ^I Cl^ ² -COE) {K ² (N',5)-la}] (M-1).

[0231] Example 7.1. Synthesis of Complex M-1. In a particular preparation, to

[IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) was added a solution of ligand la (86 mg, 0.324 mmol) in THF (4 ml) with stirring. The initially formed red solution afforded a precipitate after ca. 10 min. The mixture was stirred for 4 h at r.t. and a yellow precipitate was collected on a frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight to afford 152 mg of a yellow product (78%). Elem. Anal: Calcd for C ₂₂ H ₃₆ ClIrN ₂ OS (604.27): C, 43.73; H, 6.01 ; N, 4.64%; Found: C, 43.46; H, 5.93; N, 4.42%. If the same procedure was carried out in 3 ml of THF, the product was isolated in 90% yield. Elemental analysis for this sample, however, was not acceptable for unknown reasons: Found C, 40.85; H, 5.43; N, 3.91%. The compound is oxygen-sensitive in solution. NMR spectra of the complex depend on the nature of the solvent and are time- dependent. The compound was slightly oxygen-sensitive in solution. NMR spectra of the complex depended on the solvent. The NMR spectra were also time-dependent.

[0232] In another procedure, an orange suspension of [IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) in dichloromethane (1 ml) was prepared. A solution of ligand la (86 mg, 0.324 mmol) in dichloromethane (3 ml) was also prepared. The solution was added to the suspension. After stirring for less than about 30 seconds, a red solution formed. This was stirred for 3 hours at room temperature, then concentrated to about 2 mL, and layered with diethyl ether (20 ml).

Yellow crystals and a yellow powder formed after two days. The solids were filtered, washed with diethyl ether (3 x 5ml) and dried under vacuum dried to afford 142 of a gold-colored material identified as a CH ₂ C1 ₂ solvate of complex M-l (one molecule of solvent per 4 molecules of complex based on elemental analysis. Elem. Anal.: Calc'd for

4C ₂₂ H ₃₆ ClIrN ₂ OS CH ₂ Cl ₂ : C, 42.72; H, 5.88; N, 4.48%; Found: C, 42.55; H, 5.90; N, 4.34%.

[0233] Example 7.2. Synthesis of Complex N-2. To [IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) was added a solution of ligand 2a (91 mg, 0.324 mmol) in THF (3 ml) with stirring. The orange-yellow suspension was stirred for 3 h at r.t., and a white precipitate was collected on a frit, washed with diethyl ether (3 ^x 10 ml) and vacuum dried overnight to afford 100 mg of the final off-white product (61%). Elem. Anal : Calcd for Ci ₅ H ₂₄ ClIrN ₂ OS (508.10): C, 35.46; H, 4.76; N, 5.51%; Found (under nitrogen): C, 35.96; H, 4.75; N, 5.09%. The same compound was obtained when the synthesis was carried out in dichloromethane under the same conditions, except 6 ml of the solvent was used; 50%> isolated yield (82 mg). The compound is sparingly soluble in CD ₂ C1 ₂ (hydride peak is observed at δ -19.49 ppm), OMF-dj.

[0234] Example 7.3. Synthesis of Complex N-3. To [IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) was added a solution of ligand 4a (95 mg, 0.324 mmol) in THF (3 ml) under stirring. The initially formed red solution afforded a precipitate after ca. 2 min. The orange-yellow mixture was stirred for 3 h at r.t., and a white precipitate was collected on a frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight to afford 57 mg of the final off-white product (34%). Elem. Anal: Calcd for Ci ₆ H ₂₆ ClIrN ₂ OS (522.12): C, 36.81; H, 5.02; N, 5.37%. Found (under nitrogen): C, 37.71; H, 5.10; N, 5.05%. The compound is stable in CD ₂ CI ₂ at least overnight. 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ -21.35 (s, 1H), 1.94 (t, J~ 3 Hz, 1H), 2.27 (t, J~ 3 Hz, 1H), 2.48 (td, J~ 13 Hz, J~ 3 Hz, 1H), 2.56 (td, J~ 13 Hz, J~ 3 Hz, 1H), 2.63-2.84 (overlapped m, 3H), 2.86-3.00 (m, 1H), 3.01-3.11 (m, 1H), 3.53 (d, J~ 11 Hz, 1H), 3.61 (t, J~ 3 Hz, 1H), 3.68-3.86 (overlapped m, 5H), 3.91 (d, J~ 12 Hz, 2H), 4.07 (d, J~ 14 Hz, 1H), 4.41 (q, J~ 11 Hz, 2H), 6.77-6.92 (overlapped, 2H), 7.13 (d, J~ 7 Hz, 1H), 7.94 (d, J~ 8 Hz, 1H). ¹³ C{1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 23.1 (s, 1C), 25.6 (s, 1C), 29.0 (s, 1C), 47.1 (s, 1C), 47.6 (s, 1C), 57.9 (s, 1C), 59.9 (s, 1C), 63.7 (s, 1C), 65.6 (s, 1C), 67.2 (s, 1C), 120.4 (s, 1C), 123.0 (s, 1C), 124.6 (s, 1C), 136.5 (s, 1C), 139.4 (s, 1C), 147.5 (s, 1C).

[0235] Example 7.4. Synthesis of Complex N-4. To [IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) was added a solution of ligand 4b (100 mg, 0.324 mmol) in THF (3 ml) with stirring. The initially formed red solution afforded a precipitate after ca. 10 min. The obtained orange-yellow mixture was stirred for 3 h at r.t., after which a white precipitate was collected on a frit, washed with diethyl ether (3 x 10 ml) and vacuum dried overnight to afford 58 mg of the final off- white product (33%). Elem. Anal: Calcd for Ci ₇ H ₂₈ ClIrN ₂ OS (536.15): C, 38.08; H, 5.26; N, 5.23%. Found (under nitrogen): C, 37.77; H, 5.10; N, 5.27%>. The compound is remarkably air-stable in the solid state, but slowly decomposes in CD ₂ C1 ₂ under argon (11%> decomposition) after 15 h monitoring at room temperature. 1H NMR (400 MHz, CD ₂ C1 ₂ , r.t.): δ -22.21 (s, 1H), 1.18 (m, 1H), 1.54 (m, 1H), 1.94 (m, 2H), 2.29 (m, 2H), 2.46 (m, 2H), 1.94 (m, 2H), 2.54-2.81

(overlapped m, 4H), 3.34 (brs, 1H, NH), 3.53-4.13 (overlapped m, 8Η), 4.39 (t, J~ 11 Hz, 1H), 4.50 (t, J~ 11 Hz, 1H), 6.83 (t, J~ 7 Hz, 1H), 6.93 (t, J~ 7 Hz, 1H), 7.12 (d, J~ 7 Hz, 1H), 7.82 (d, J~ 7 Hz, 1H). ¹³ C {1H} (100.5 MHz, CD ₂ C1 ₂ , r.t.): δ 23.5 (s, 1C), 25.9 (s, 1C), 32.3 (s, 1C), 49.7 (s, 1C), 51.1 (s, 1C), 55.1 (s, 1C), 60.3 (s, 1C), 61.6 (s, 1C), 63.7 (s, 1C), 64.0 (s, 1C), 64.4 (s, 1C), 121.0 (s, 1C), 121.5 (s, 1C), 125.3 (s, 1C), 135.5 (s, 1C), 139.2 (s, 1C), 148.9 (s, 1C).

[0236] Example 7.5. Synthesis of Complex N-5. To [IrCl(COE) ₂ ] ₂ (145 mg, 0.162 mmol) was added a solution of ligand 6 (104 mg, 0.324 mmol) in toluene (2 ml), then acetonitrile (2 ml) with stirring. The initial orange suspension converted into a red solution upon stirring. The mixture was stirred for 3 h at r.t., concentrated to ~ half volume and layered with pentane (22 ml). In 4 days, the mother liquor was decanted from the residue composed of red- yellow crystalline material (bottom) and well-shaped yellow crystals (wall). The residue was slightly dried and diethyl ether (5 ml), then pentane (5 ml), were added successively and the resulting suspension was stirred -10 min. The binary solvent was decanted and the yellow powder was washed two times with diethyl ether (5 ml) and then dried overnight under vacuum. Isolated yield: 141 mg (79%). Elem. Anal: Calcd for Ci ₈ H ₃ oClIrN ₂ OS (550.18): C, 39.30; H, 5.50; N, 5.09%. Found (under nitrogen): C, 39.14; H, 5.62; N, 5.29%. 1H NMR (400 MHz, CDCls, r.t.): δ -25.02 (s, 1H), 1.38-1.51 (m, 1H), 1.60-1.76 (m, 2H), 1.96-2.10 (m, 1H), 2.10- 2.19 (m, 1H), 2.19-2.30 (m, 1H), 2.42-2.59 (m, 6H), 2.67-2.81 (m, 2H), 2.81-2.91 (m, 1H), 2.57-2.72 (m, 2H), 3.72-3.88 (m, 4H), 3.88-4.00 (m, 2H), 4.37 (q, J~ 10 Hz, 2H), 6.77 (t, J~ 7 Hz, 1H), 6.84 (t, J~ 7 Hz, 1H), 7.03 (d, J~ 7 Hz, 1H), 7.98 (d, J~ 7 Hz, 1H). ¹³ C {1H} (100.5 MHz, CDCI ₃ , r.t.): δ 15.3 (s, 1C), 22.4 (s, 1C), 24.7 (s, 1C), 36.0 (s, 1C), 50.0 (s, 1C), 54.4 (s, 1C), 59.4 (s, 1C), 60.2 (s, 1C), 61.1 (s, 1C), 61.2 (s, 1C), 64.2 (s, 1C), 64.3 (s, 1C), 120.1 (s, 1C), 120.9 (s, 1C), 124.0 (s, 1C), 133.2 (s, 1C), 138.5 (s, 1C), 149.3 (s, 1C).

[0237] Example 7.6. Synthesis of Complex N-l . Prepared similarly as N-5, except 7 was used as ligand. Isolated yield: 141 mg (79%>). Elem. Anal: Calcd for Ci ₈ H ₃ oClIrN ₂ OS (508.14): C, 37.82; H, 5.55; N, 5.51%. Found (under nitrogen): C, 37.53; H, 5.33; N, 5.47%. Slowly decomposes in CDC1 ₃ . 1H NMR (400 MHz, CDC1 ₃ , r.t., selected): δ -25.37 (s, 1H), 6.73 (t, J~ 7 Hz, 1H), 6.81 (t, J~ 7 Hz, 1H), 7.00 (d, J~ 7 Hz, 1H), 8.00 (d, J~ 7 Hz, 1H). ¹³ C {1H} (100.5 MHz, CDC1 ₃ , r.t.): δ 23.9 (s, 1C), 24.8 (s, 1C), 36.9 (s, 1C), 50.6 (s, 1C), 53.9 (s, 1C), 54.5 (s, 1C), 59.5 (s, 1C), 59.6 (s, 1C), 60.9 (s, 1C), 61.6 (s, 1C), 1 19.4 (s, 1C), 120.5 (s, 1C), 123.7 (s, 1C), 135.6 (s, 1C), 138.8 (s, 1C), 149.8 (s, 1C).

[0238] The reactivity of [IrCl(r| ² -COE) ₂ ] ₂ towards NNS-type ligands la, 2a, 4a and 4b was in sharp contrast to its reported reactivity towards PNP-type ligands of the general formula type R ₂ P(CH ₂ ) ₂ NH(CH ₂ ) ₂ PR ₂ , (the outcome of these reactions also depended on the nature of R and the reaction conditions, including solvent and temperature). When R = 'Pr,

[Ir ⁿⁱ ClH ₂ { Pr ₂ PC ₂ H4) ₂ NH}] was isolated when the synthesis was carried out in isopropanol at 80 °C. At room temperature, the reaction was reported to give the complex [ΐΓ ^! (η ² - COE) {('Pr ₂ PC ₂ H4) ₂ NH}]Cl, which was reported to exhibit fluxional behavior in solution. When R = Cy or Ad, isostructural iridium (III) dihydride complexes [Ir ⁱⁿ ClH ₂ {(Cy ₂ PC ₂ H ₄ ) ₂ NH}] and [Ir ⁱⁿ ClH ₂ {(Ad ₂ PC ₂ H ₄ ) ₂ NH}] were isolated when the reaction was carried out at room temperature in toluene and THF, respectively. When R = bulky ^t Bu,

[IrCl(C ₈ Hi ₃ )H{( ⁱ Bu ₂ PC ₂ H4) ₂ NH}] was isolated. The [Ir ⁱⁿ ClH ₂ {CPr ₂ PC ₂ H ₄ ) ₂ NH}] ("Ir-PNP") is commercially available and has been reported as (pre)catalyst in ester hydrogenation, ketone transfer hydrogenations, solvolysis of ammonia borane and amination of aliphatic alcohols.

[0239] The identity of embodiment complexes M-1 and N-l, N-2, N-3, N-4, N-5 was supported by elemental analysis. In addition, X-ray structures were obtained for complexes M-1, N-3, N-4 and N-5, respectively.

[0240] Example 8. Synthesis and Characterization of Other Complexes Using NNS, P(0)NS, SNNS Type Ligands

[0241] Other transition metal complexes are accessible by reactions of suitable precursors with these inventive ligands. Representative inventive complexes were also prepared using first row transition metals including Mn, Fe, Co, Ni, and Cu. These reactions typically involved reaction of the embodiment ligand with a MCb salt (M = transition metal) in a solvent at 25°C. Chart 8 below illustrates other complexes of NNS, P(0)NS, SNNS-type ligands that were synthesized, isolated and subsequently used as precatalysts in catalytic reactions.

Chart 8.

Mn-1 Fe-1 Co-1 Co-2

possible structure

Ni-1 Cu-1 Cu-2

possible structure possible structure possible structure

-2 Co-3 Cu-3

Cu-4 Cu-5

[0242] Complexes Mn-1, Fe-1, Fe-2, Co-1, Co-2, Co-3, Ni-1, Cu-1, Cu-2, Cu-3, Cu-4, and Cu-5 were synthesized according to Scheme 12 and Scheme 13.

1 1 Cll-5 y. 75%

Scheme 13. Synthesis of several exemplary copper complexes. Isolated yields are shown.

[0243] Example 8.1. Synthesis of [Mn(K ² [ V, V]-la)Cl ₂ ] (Mn-1). To a pink suspension of MnCl ₂ (0.745 mmol, 94 mg) in MeCN (1 ml) was added a solution of la (0.745 mmol, 198 mg) in MeCN (3 ml) under stirring. In 1-2 min, white precipitate started to form. In 24 h, the precipitate was filtered, washed with MeCN (3 x 2 ml), diethyl ether (3 ^x 4 ml) and vacuum dried overnight. Yield: 220 mg (75 %), white powder. The compound is sparingly soluble in dichloromethane, THF, ethanol and acetonitrile. It dissolves immediately in water on air. The obtained transparent solution slowly produces yellowish precipitate likely due to decomposition. Elem. Anal: Calcd for (1568.96): C, 42.87; H, 5.65; N, 7.14%; Found (under nitrogen): C, 42.06; H, 5.34; N, 6.92%. ^ = 6.4 μ _Β (21 °C).

[0244] Example 8.2. Iron complexes

[0245] Example 8.2.1. Synthesis of [Fe(K ² [7V,7V]-la)Cl ₂ ] (Fe-1). To a yellowish suspension of FeCl ₂ (0.745 mmol, 94 mg) in MeCN (1 ml) was added a solution of la (0.745 mmol, 198 mg) in MeCN (3 ml). The initial suspension slowly transformed into a light-green solution (ca. 1 h). In 2 h, the solution was filtered through a Whatman syringe filter (PTFE membrane, pore size 0.45 μιη), concentrated to ~ 2 ml and layered with diethyl ether (~ 21 ml). Large light-green-blue box-crystals were obtained overnight. Decantation of the mother liquor after 5 days afforded 223 mg of the compound (76 %). Elem. Anal: Calcd for Ci ₄ H ₂₂ Cl ₂ FeN ₂ OS (393.15): C, 42.77; H, 5.64; N, 7.13%; Found (under nitrogen): C, 42.12; H, 5.45; N, 6.78%. = 5.5 μ _Β (21 °C).

[0246] Alternative work-up for Fe-1. After filtering the solution through a Whatman syringe filter as described above, the solvent was evaporated and the obtained residue was stirred with diethyl ether (7 ml) - pentane (7 ml) mixture to afford a white precipitate (overnight). The precipitate was collected, washed with diethyl ether (3 >< 5 ml) and vacuum dried overnight. Yield: 215 mg (73 %), white powder. The paramagnetic material is oxygen-sensitive in both the solid state and immediately in solution. Elem. Anal.: Calcd for C ₁₄ H ₂₂ Cl ₂ FeN ₂ OS (393.15): C, 42.77; H, 5.64; N, 7.13%. Found (under argon): C, 42.59; H, 5.69; N, 7.01%.

[0247] Example 8.2.2. Synthesis of Complex Fe-2. To yellowish FeCl ₂ (0.221 mmol, 28 mg) was added a solution of ligand 8 (0.221 mmol, 70 mg) in MeCN (3 ml) under stirring. The obtained solution was stirred for 2 h and layered with diethyl ether (20 ml). The next day a white precipitate was separated, washed with diethyl ether (3 >< 5 ml) and vacuum dried. Yield: 67 mg (68%), off-white powder. Elem. Anal: Calcd for CnffeCbFeNOPS (446.15): C, 45.77; H, 4.97; N, 3.14%; Found: C, 45.48; H, 4.95; N, 3.06%.

[0248] Example 8.3. Cobalt Complexes

[0249] Example 8.3.1. Synthesis of [Co(K ² [ V, V]-la)Cl ₂ ] (Co-1). To a blue suspension of CoCl ₂ (0.745 mmol, 97 mg) in MeCN (1 ml) was added a solution of la (0.745 mmol, 198 mg) in MeCN (3 ml). The obtained solution was stirred for 2 h, filtered through Whatman syringe filter (PTFE membrane, pore size 0.45 μιη), concentrated to ~ 2 ml and layered with diethyl ether (~ 21 ml). Blue crystals were obtained overnight. Decantation of the mother liquor after 5 days afforded 236 mg of a visually air-stable compound (80 %). Elem. Anal.: Calcd for C ₁₄ H ₂₂ CI ₂ C0N ₂ OS (396.24): C, 42.44; H, 5.60; N, 7.07%; Found: C, 42.27; H, 5.63; N, 7.08%. ^ = 5.1 μ _Β (21 °C).

[0250] Example 8.3.2. Synthesis of [Co( ³ [ V, V',S]-3a)Cl ₂ ] (Co-2). To a blue suspension of C0CI ₂ (0.745 mmol, 97 mg) in MeCN (1 ml) was added a solution of 3a (0.745 mmol, 209 mg) in MeCN (3 ml). Additionally MeCN (3 ml) was added to the obtained mixture was for homogenization. The thus obtained blue solution was stirred for 2 h, concentrated to ~ half of the volume and layered with diethyl ether (~ 17 ml). Light-blue crystals were obtained overnight. Decantation of the mother liquor afforded 186 mg of visually air-stable compound (61 %). Elem. Anal: Calcd for Ci ₅ H ₂₄ Cl ₂ CoN ₂ OS (410.26): C, 43.91 ; H, 5.90; N, 6.83%; Found: C, 44.21 ; H, 5.92; N, 6.80%. ^ = 4.4 μ _Β (25 °C).

[0251] Example 8.3.3. Synthesis of Complex Co-3. To CoCl ₂ (0.209 mmol, 27 mg) was added a solution of ligand 8 (0.209 mmol, 1 15 mg) in MeCN (4 ml). The obtained blue solution was stirred for 2 h, filtrated and layered with diethyl ether (20 ml). The next day aprecipitate collected, washed with diethyl ether (3 >< 5 ml) and dried under vacuum overnight. Yield: 66 mg (70%). Elem. Anal: Calcd for Ci ₇ H ₂₂ Cl ₂ CoNOPS (449.24): C, 45.45; H, 4.94; N, 3.12%; Found: C, 45.33; H, 4.87; N, 3.18%.

[0252] Example 8.4. Synthesis of irans-[Ni( 3[N,N',S]-3a)(EtOH)Cl ₂ ] (Ni-1). A mixture of NiCl ₂ (0.278 mmol, 36 mg) and 3a (0.278 mmol, 79 mg) in anhydrous EtOH (4 ml) was stirred in a KONTES® pressure tube at 90°C. After 44 h, the tube was cooled at -20°C for 1 h, and a greenish precipitate was collected on a frit filter, washed with EtOH (3 x 2 ml), then Et20 (3 x 4 ml) and dried under vacuum overnight. 77 mg of the greenish powder was recovered (61 %). Elem. Anal : Calcd for Ci ₇ H ₂₂ Cl ₂ NiNOPS (456.09): C, 44.77; H, 6.63; N, 6.14%; Found (under nitrogen): C, 45.03; H, 6.50; N, 6.06%. ^ _ff = 3.6 μ _Β (25 °C).

[0253] Example 8.5. Copper complexes

[0254] Example 8.5.1. Synthesis of [Cu(K ³ [ V, V',S]-3a)Cl ₂ ] (Cu-1). To a brown suspension of CuCl ₂ (0.745 mmol, 100 mg) in MeCN (1 ml) was added a solution of 3a (0.745 mmol, 198 mg,) in MeCN (3 ml). An immediate change of the color to green was observed. The obtained solution was stirred for 4 h, filtered and the solvent evaporated under vacuum. To the obtained oily residue was added pentane (10 ml), and the mixture was stirred overnight to afford a green precipitate that was collected, washed with pentane and dried under vacuum overnight. Yield: 272 mg (91%), visually air- and moisture-stable green solid. Elem. Anal.: Calcd for Ci ₄ H ₂₂ Cl ₂ CuN ₂ OS (400.85): C, 41.95; H, 5.53; N, 6.99%; Found: C, 41.88; H, 5.53; N, 6.84%. ^ = 2.1 μ _Β (25 °C).

[0255] Example 8.5.2. Synthesis of [Cu( ³ [ V, V',S]-3a)Cl ₂ ] (Cu-2). To a brown suspension of CuCl ₂ (0.684 mmol, 92 mg) in MeCN (2 ml) was added a solution of 3a (0.684 mmol, 192 mg) in MeCN (6 ml). An immediate change of the color to green was observed. The obtained suspension was stirred for 4 h, the precipitate was filtered washed with diethyl ether (3 x 5 ml) and dried under vacuum overnight. Yield: 224 mg (79%), as an air- and moisture-stable sea-green solid. Elem. Anal: Calcd for Ci ₅ H ₂₄ Cl ₂ CuN ₂ OS (414.88): C, 43.43; H, 5.83; N, 6.75%; Found: C, 42.83; H, 5.49; N, 6.58%. = 1.9 μ _Β (25 °C).

[0256] Example 8.5.3. Synthesis of Complex Cu-3. To a brown CuCl ₂ (0.358 mmol, 48 mg) was added a solution of ligand 8 (0.358 mmol, 115 mg) in MeCN (4 ml). A change in color to green was observed (~5 min). The obtained mixture was stirred for 2 h, filtered and the filtrate was layered with diethyl ether (20 ml). The next day, a precipitate was collected, washed with diethyl ether (3 >< 5 ml) and dried under vacuum overnight. Yield: 122 mg (75%). Elem. Anal.: Calcd for Ci ₇ H ₂₂ Cl ₂ CuNOPS (453.85): C, 44.99; H, 4.89; N, 3.09%; Found: C, 43.92; H, 4.89; N, 3.03%.

[0257] Example 8.5.4. Synthesis of Complex Cu-4. To a brown suspension of CuCl ₂ (98 mg, 0.729 mmol) in MeCN (2 ml) was added a solution of 10 (153 mg, 0.729 mmol) in MeCN (4 ml). An immediate change of the color to blue was observed. In 10 min, the color changed to dark purple and a cyan precipitate started to form under stirring. The obtained suspension was stirred for 2 h, the precipitate was filtered, washed with pentane (3 x 5 ml) and dried under vacuum overnight. Yield: 186 mg (74%), air- and moisture-stable cyan solid. Elem. Anal: Calcd for CnHi ₈ Cl ₂ CuN ₂ S (344.79): C, 38.32; H, 5.26; N, 8.12%; Found: C, 38.04; H, 5.11; N, 8.06%). Upon dissolution in different solvents, different colors of solutions are observed: cyan in methanol, yellow in benzene, green in THF.

[0258] Example 8.5.5. Synthesis of Complex Cu-5. To a brown suspension of CuCl ₂ (40 mg, 0.298 mmol) in MeCN (2 ml) was added a solution of 11 (104 mg, 0.298 mmol) in MeCN (2 ml). Immediate change of the color to green was observed. In ~1 min, a precipitate started to form under stirring. The obtained suspension was stirred for 2 h, the precipitate was filtered, washed with diethyl ether (3 x 5 ml), pentane (3 x 5 ml) and dried under vacuum overnight. Yield: 111 mg (77%), light-green air- and moisture-stable solid. Elem. Anal.: Calcd for Ci ₉ H ₂₆ Cl ₂ CuN ₂ S ₂ (481.00): C, 47.44; H, 5.45; N, 5.82%; Found: C, 46.48; H, 5.33; N, 5.76%.

[0259] Example 8.5.6. Synthesis of Water-Soluble Complex Cu-6 and unique dimeric Cu-7 complex containing two chiral ligands as shown in Scheme 14.

Scheme 14.

[0260] Example 8.5.6.1. Synthesis of Water-Soluble Complex Cu-6. CuS0 ₄ 5H ₂ 0 (500 mg, 2.0 mmol) was dissolved in MeOH (30 ml, -20 min) under stirring. A solution of ligand 10 (421 mg, 2.0 mmol) in MeOH (10 ml) was added. An immediate change of the color to blue-dark was observed. The mixture was stirred in air for 2 h, the precipitate was filtered, washed with MeOH (3 x 10 ml), diethyl ether (3 x 25 ml) and vacuum dried to afford 660 mg of the product. Elem. Anal: Calcd for CiiHi ₈ Cl ₂ CuN ₂ 0 ₄ S2 (369.95): C, 35.71 ; H, 4.90; N, 7.57%; Found: C, 34.65; H, 4.69; N, 6.96%>. The product was air and moisture-stable.

[0261] Example 8.5.6.2. Synthesis of Complex Cu-7. To a suspension of (£)-(+)- Ι , - Binaphthyl-2,2'-diyl hydrogenphosphate (97% Aldrich, CAS Number 35193-64-7, 200 mg, 0.574 mmol) in 15 ml of dichloromethane was added a solution of Cu-6 (0.5 equiv, 106 mg, 0.287 mmol) in 10 ml of water. The mixture was stirred in air and NaHC0 ₃ was added via spatula until two clear phases formed. Brine (5 ml) was added. The blue organic phase was separated. The aqueous phase was washed with dichloromethane (2 x 15 ml). Combined organic phases were dried over MgS04, filtered and vacuum dried to afford 146 mg of the product (52 % yield). The complex easily recrystallized from hot acetone on air. Elem. Anal.: Calcd for Cio ₂ H ₈₆ Cu ₂ N ₄ Oi ₇ P ₄ S ₂ (1954.93): C, 62.67; H, 4.43; N, 2.87%; Found: C, 59.93; H, 4.44; N, 3.02%. This product has also been characterized chrystallographically.

[0262] Example 9. Catalytic Hydrogenation of Methyl Trifluoroacetate (Scheme

15).

[0263] Complexes of the present invention were used as pre-catalysts for hydrogenation of methyl trifluoroacetate (MTFA, substrate A) as shown below. It should be appreciated that the hydrogenation of methyl trifluoroacetate by catalysts of the present invention is sufficiently novel that the catalytic hydrogenation of this substrate constitutes separate embodiments of the present invention.

[0264] Results are summarized in Table 1 (vide infra).

"MTFA" "TFAMH" "TFE"

A B c

Scheme 15.

[0265] In one set of experiments, the ester methyl trifluoroacetate ("MTFA") was chosen as a substrate because homogeneous hydrogenation of MTFA may afford

trifluoroacetaldehyde methyl hemiacetal ("TFAMH") and/or 2,2,2-trifluoroethanol ("TFE") depending on the conditions used. TFAMH is an important synthon in the production of various fluorinated chemicals containing CF ₃ -groups. TFAMH is also used in medicinal chemistry and in agrochemical research and in materials research. MTFA is typically produced from fluoral and methanol at -78 °C, or via a complicated two-step Swartz-type reaction (including a step with HF in the gas-phase), or by stoichiometric hydrogenation of MTFA using borohydride as a reducing agent. The borohydride reduction is neither environmentally nor economically attractive. A method for catalytically converting MTFA (commercially available at $47 for 25 grams) into TFAMH (commercially available at $50 for 250 milligrams) using molecular hydrogen would provide a less expensive, greener alternative to the known methods.

Table 1. Hydrogenation of methyl trifluoroacetate A catalyzed by various bifunctional catalysts" . run cat S/C temp, °C conv., %* yield, % ^b B C TON ^c

1 - - 40 0 0 0 0 0

2 Ru-MACHO 2000 40 92 92 1 91 3660

3 Ru-MACHO 20 000 40 96 96 72 24 24000

4 Ru-SNS 2000 40 71 71 59 12 1660

5 Ru-P N 2000 40 43 42 41 1 860

6 (^,^)-Ts-DENEB 2000 40 26 26 21 5 620

7 (^)-RUCY-XylBINAP 2000 40 62 62 44 18 1600

8 A-l 2000 40 53 52 35 17 1380

9 A-2 2000 40 69 69 42 27 1920

10 A-3 2000 40 77 77 57 20 1940

11 A-6 2000 40 46 45 31 14 1180

12 J-l 2000 40 20 20 ^rf 19 1 420

13 J-2 2000 40 27 26 ^rf 22 4 600

14 L-l 2000 40 39 38 ^rf 25 13 1020

15 B-l 2000 40 66 66 39 27 1860

16 C-2 2000 40 60 60 36 23 1640

17 A-4 2000 40 88 87 75 12 1980

18 K-l 2000 40 50 49 46 3 1040

19 A-5 2000 40 36 35 ^e 34 1 720

20 D-l 2000 40 72 71 61 10 1620

21 Ir-PNP 2000 ^' 40 97 97 13 84 3620

22 Ir-PNP 20 000 40 86 86 51 35 24200

23 M-l 2000 40 90 90 75 15 2100

24 M-l 20 000 40 29 29 27 1 5800

25 N-2 2000 42^46 96 96 68 27 2440

26 N-2 20 000 40 58 58 56 1 11600

27 N-3 2000 42^46 96 96 44 51 2920

28 N-3 20 000 40 58 58 56 1 11600

29 N-4 2000 40 91 91 62 29 2400

30 N-4 20 000 40 53 53 51 2 11000

31 N-4 20 000 ⁵ 40 0.3 0.3 0 0.3 120

"Experimental conditions: substrate (10 mmol), 5 ml MeOH containing 2.5 mmol MeONa (135 mg), 24 h, 50 ml Parr autoclave. ^¾19 F NMR area, see SI for details. "TON = turnover number, calculated as TON (B) + 2 x TON (C). ^Reaction mixture was heterogeneous in the end. ^e Reaction mixture became green upon exposure to air. -¾0 min. ^• ¾ase = 13.5 mg (0.025 equiv relative to A). Chart 9

N-5 R = Me; n = m = 2

[0266] Entries 2-7, 20-21 in Table 1 describe results obtained using various

commercially available Ru and Ir complexes as shown in Chart 9. Entries 8-19, 22-27 represent the results obtained with embodiment complexes under the same conditions. Since the vast majority of esters (and other carboxylic and carbonic acid derivatives) are methyl derived, methanol was chosen as the solvent. The reduction of these compounds will necessarily produce methanol, thus its direct use as the reaction medium greatly simplifies solvent recycle. In this case, no solvent separation steps are required, thus positively impacting environmental aspects of such chemistries (a very important consideration in pharmaceutical and large-scale industrial processes). Unfortunately, many bifunctional catalysts, in particular those used for ester hydrogenations, are not active in methanol. For example, Gusev's Ru-SNS complex that is a versatile catalyst for ester hydrogenation in THF (WO2014036650A1), hydrogenates substrate A only barely in methanol. Results from Table 1 identify three versatile catalysts for the A hydrogenation in methanol, Ru-MACHO complex, Ir-PNP and complexes N-2, N-3 and N-4. Of note catalyst N-5 (see below, Table 2), gives excellent selectivity towards B formation (96%) and reasonable TON of 19 000.

[0267] Example 9.1. Hydrogenation under substrate-to-catalyst ratio (S/C) = 2000. In a closed vial (loaded in the glovebox), a mixture of complex (0.005 mmol) and MeONa (135 mg, 2.5 mmol) was stirred in methanol (5 ml) for approximately 1 min (except for J-l and J-2, which were stirred for approximately 15 min to ensure complete dissolution). Methyl

trifluoroacetate A (1 ml, 10 mmol) was added via microsyringe and the resulting mixture was stirred for approximately 1 minute more and then transferred into a 50 ml Parr autoclave (Model No. 4792 General Purpose Vessel with a PTFE head gasket) equipped with glass liner and magnetic stirrer. The autoclave was closed, removed from the glovebox and connected to a hydrogen tank (the line was vented with molecular hydrogen three times). Hydrogen was initially introduced into the autoclave at a pressure of approximately 5 bar, before being reduced to approximately 1 bar by carefully releasing the stop valve three times and finally pressurized to 25 bar. The temperature was carefully increased to 40°C and monitored via a 4838 Parr

Temperature Controller. Observed stability and accuracy was ±1°C. At the end of the reaction time, the reactor was moved into a precooled water bath (0°C) for 5-10 min and then

depressurized. The neat reaction mixture from the liner was then directly analyzed by ¹⁹ F NMR spectroscopy (rd = 10 s; trifluoroacetaldehyde methyl hemiacetal ("TFAMH," B): δ -83.3, d, ³ JF-H = 4 Hz; 2,2,2-trifiuoroethanol ("TFE,"C): δ -77.0 ppm, t, ³ J _F - _H = 9 Hz). We noted in some experiments, a very minor amount of acetal (< 0.5-1%, ¹⁹ F NMR: δ -80.5, d, JF-H = 4 Hz). The balance of material present was unreacted starting material. Most of the experiments were performed at least twice.

[0268] Example 9.2. Hydrogenation under substrate-to-catalyst ratio (S/C) = 20,000. A stock solution of the complex (0.005 mmol) in methanol (10 ml) was prepared. 1 ml of this stock-solution was added to a mixture of MeONa (135 mg, 2.5 mmol or 13.5 mg, 0.25 mmol) in 4 ml MeOH. The mixture was stirred for approximately 1 min prior to addition of methyl trifluoroacetate (1 ml, 10 mmol). Further manipulations were performed as described above for hydrogenations performed with S/C=2000.

[0269] A second set of experiments, focusing on two iridium complexes to verify the effect of methylation of the NH ligand, as well as the amount of base, are described in Table 2. Table 2

run Ir cat S/C base, equiv" conv., % ^b yield, % ^b B C TON ^c

1 - - - 0 0 0 0 0

2 N-4 2000 500 91 91 62 29 2400

3 N-4 5000 1250 84 83 74 9 4600

4 N-4 20000 5000 53 53 51 2 11000

5 N-4 2000 ^c 50 13 13 12 1 280

6 N-4 5000 ^c 125 1.7 1.7 1.7 0 85

7 N-4 20000 ^c 500 0.3 0.3 0.3 0 60

8 N-5 2000 500 92 92 60 32 2480

9 N-5 5000 1250 92 92 78 14 5300

10 N-5 20000 5000 91 91 87 4 19000

1 1 N-5 2000 ^c 50 -2.5 -2.5 2.5 -0.04 -52

12 N-5 5000 ^c 125 0.9 0.9 0.9 0 45

13 N-5 20000 ^c 500 0.2 0.2 0.2 0 40

"Relative to [Ir]. ^bl9 F NMR area of neat reaction mixture, see SI. TON = turnover number, calculated as TON (B) + 2 TON(C). ^c Ester:base = 1 :0.025.

[0270] Entries 2-7 and 8-13 in Table 2 summarize results obtained from using complexes N-4 and N-5, respectively.

[0271] Runs 4 and 10 provide a comparison of hydrogenation rates of complex N-4 with complex N-5 under otherwise identical reaction conditions. Turnover numbers (TON) for these runs were excellent, exceeding 10,000. Notably, replacement of the NH group of complex XVIII with the N(C¾) group of complex N-5 resulted in an almost 60% increase in hydrogenation activity. This difference in hydrogenation activity between complex N-4 and complex N-5 was unexpected because it is contrary to what would have been expected based upon the generally accepted behavior and mechanism for bifunctional catalysis in which N-methylated complexes are much less active (if at all) for hydrogenation than their corresponding NH analogs.

[0272] Example 10. Catalytic Hydrogenation of Aromatic Ketones (Scheme 16).

The results are summarized in Table 3. Again, the results are focusing on two iridium complexes to verify the effect of methylation of the NH ligand.

Scheme 16.

Table 3. Catalytic Hydrogenation of Aromatic Ketones.'

Run cat subs S/C MeONa, Solv time, h temp, conv. yield, mol % °C % ^b % ^b l ^c N-4 Kl 5 000 5 MeOH 0.5 ^d 40-41 100 100

2 ^C N-5 Kl 5 000 5 MeOH 0.5 ^d 40 100 100

3 ^C N-4 Kl 50 000 5 MeOH 3 40-41 58 58

4 ^C N-5 Kl 50 000 5 MeOH 3 40 >99 >99

5 N-4 K2 50 000 5 MeOH 3 40-42 9 9

6 N-5 K2 50 000 5 MeOH 3 40 26 26

7 N-4 K3 1 000 5 MeOH 1 40 >99 >99

8 N-5 K3 1 000 5 MeOH 1 40 >99 >99

9 N-4 K3 50 000 5 MeOH 3 40-42 25 25

10 N-5 K3 50 000 5 MeOH 3 40-42 27 27

11 N-4 K4 50 000 5 MeOH 3 40-43 ~0 ~0

12 N-5 K4 50 000 5 MeOH 3 40-43 ~0 ~0

13 N-4 K5 1 000 5 MeOH 3 40 ~0 ~0

14 N-5 K5 1 000 5 MeOH 3 40 ~0 ~0

15 N-4 K6 1 000 5 MeOH 3 40-42 100 100

16 N-5 K6 1 000 5 MeOH 3 40-42 100 100

Standard reaction conditions: substrate (10 mmol), solvent (5 mL), 50 mL Parr autoclave. *NMR (1H or ¹⁹ F, rd = 10 s). ^c Each run performed at least twice, see SI for details. ^Essentially completed after 20 min based on drop in pressure. [0273] Example 11. Catalytic Hydrogenation of 2,2,2-trifluoroacetophenone. The catalyst (0.008 mmol: complex N-4: 4.3 mg, complex N-5: 4.4 mg) was dissolved in methanol (20 ml) with stirring. 5 ml of this stock-solution was added to MeONa (5 mol %: 27 mg). The mixture was stirred for ~1 min prior to addition of 2,2,2-trifluoroacetophenone (1.4 ml, 10 mmol). The obtained mixture was then stirred for ~1 min additionally and then transferred into a 50 ml Parr autoclave (Model No. 4792 General Purpose Vessel with a PTFE head gasket) equipped with glass liner and magnetic stirrer. The autoclave was closed, removed from the glovebox, connected to a hydrogen tank (the line was vented with molecular hydrogen three times). Hydrogen was initially introduced into the autoclave at a pressure of ~5 bar, before being reduced to ~1 bar by carefully releasing the stop valve (3 times) and finally pressurized to 25 bar. The temperature was gently increased to 40 °C and monitored via a 4838 Parr Temperature Controller. Observed stability and accuracy was ±2 °C. In 30 min, the reactor was moved into a precooled water bath (0 °C) for 5 min and then depressurized. The neat reaction mixture from the liner was then directly analyzed by 1H and ¹⁹ F NMR spectroscopy without lock. The balance of material present was unreacted 2,2,2-trifluoroacetophenone ( ¹⁹ F).

[0274] Example 11.1. Transfer Hydrogenation of 2,2,2-trifluoroacetophenone (Scheme 17).

Scheme 17.

[0275] Under argon, to a mixture of complex N-l (2.7 mg) in 2.5 ml of formic acid- triethyl amine (5:2 azeotropic mixture, Sigma Aldrich, CAS Number 15077-13-1) was added 2,2,2-trifluoroacetophenone (5 mmol, 700 mkl) over microsyringe. The solution was stirred for 1 week (the vial was periodically opened under argon to decrease pressure due to C0 ₂ evolution) at room temperature and measured. Full (100%) conversion was observed by NMR spectroscopy.

[0276] Although the present invention has been described with reference to specific details, it is not intended that such details should be regarded as limitations upon the scope of the invention, except as and to the extent that they are included in the accompanying claims. As those skilled in the art will appreciate, numerous modifications and variations of the present invention are possible in light of these teachings, and all such are contemplated hereby. For example, in addition to the embodiments described herein, the present invention contemplates and claims those inventions resulting from the combination of features of the invention cited herein and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.

[0277] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.