The present invention relates to a method for the (reductive) N-methylation of nitrogen-containing organic compounds, especially amines, amides and imines.

The methylation of these compounds is synthetically interesting due to the importance of many of these compounds e.g. as bioactive compounds or pharmaceuticals. The conventional methods include alkylation reagents such as methyliodide or dimethylsulfate or the Eschweiler-Clark-reaction.

However, due to the significance of this reaction there is a constant need in the art for alternative methylation methods of nitrogen-containing organic compounds.

This object is achieved in the present invention by a method for the N-methylation of nitrogen- containing organic compounds, comprising the step of: a) reacting the nitrogen-containing organic compound with CO2 and H ₂ in the presence of a Ruthenium-Phosphine-complex

The term "nitrogen-containing organic compound" in the sense of the present invention especially means organic compounds which contain a nitrogen in the formal oxidation state (<0), e.g. primary and secondary amines, amides, imines and imides. Especially preferred - although not limiting - are aromatic amines, amides, imines and imides since it has been observed for many of these compounds that these are especially suitable for the inventive method.

CO2 and/or H ₂ are usually used as gases. However, this is not limiting and the reaction may also be used in applications where either CO2 and/or H ₂ are set free or (at least formally) made from precursor compounds or in reactions, including transfer hydrogenations. CO2 can also be used as solvent, i.e. the CO2 would be in liquid or near or supercritical form then.

The term "phosphine" in the sense of the present invention especially means and/or includes trivalent phosphororganic compounds, especially compounds with the general formula PR R ² !^ R ¹ to R ³ being independent from each other an organic residue such as e.g. a substituted or unsubstituted alkyl, aryl and/or heteroaryl.

The term "Ruthenium-Phosphine-complex" especially means and/or includes a ruthenium complex where in the coordination sphere of the ruthenium a trivalent phosphororganic component is present so that a bond (may it be a covalent and/or a coordination bond) between the ruthenium and the trivalent phosphororganic component is formed at least temporarily during the reaction. Surprisingly it has been found that by doing so it is possible to methylate the nitrogen-containing compound, using only CO ₂ and H ₂ as sources. It should be noted that in case the nitrogen-containing compound is an imine or amide, usually also reduction of the imino or amido-function to amines occurs. Therefore in these cases the method is a reductive N-methylation method. For most applications within the present invention, at least one of the following advantages could be observed:

The reaction can be used on an industrial scale as well as on a small scale

The reaction is easily adaptable to various applications and their demands

The reaction tolerates many functional groups - The reaction is atom-efficient, using CO ₂ as carbon source

It should be noted that the Ruthenium-Phosphine-complex may be used as a homogenous catalyst or in immobilized form. Also two-phase systems and phase-transfer-catalysis may be used depending on the actual application of the invention. Besides a reaction in batch mode, also a continuous reaction system is possible. It should furthermore be noted that the Ruthenium-Phosphine-complex may include other ligands such as (but not limited to) carbene, nitrogen containing-ligands such as amines or amides, phosphites, phosphoamidites, phosphoric ethers or esters, sulfides etc.

According to a preferred embodiment of the present invention, step a) is performed under acidic conditions. This has been shown to greatly increase the efficiency for most applications within the present invention.

The term "acidic conditions" in the sense of the present invention especially means and/or includes that during the reaction at least temporarily more acid than base is present.

According to a preferred embodiment the Phosphine in the Ruthenium-Phosphine-Complex is a Tri(hetero)aryl and/or Bi(hetero)arylalkyl-Phosphine. These compounds have proven themselves in practice.

Generic group definition: Throughout the description and claims generic groups have been used, for example alkyl, alkoxy, aryl. Unless otherwise specified the following are preferred groups that may be applied to generic groups found within compounds disclosed herein: alkyl: linear and branched Cl-C8-alkyl, alkenyl: C2-C6-alkenyl, cycloalkyl: C3-C8-cycloalkyl, alkoxy: Cl-C6-alkoxy, alkylene: selected from the group consisting of: methylene; 1 , 1 -ethylene; 1 ,2-ethylene; 1,1- propylidene; 1 ,2-propylene; 1,3- propylene; 2,2-propylidene; butan-2-ol-l,4-diyl; propan-2-ol-l,3- diyl; 1, 4-butylene; cyclohexane-l,l-diyl; cyclohexan-l,2-diyl; cyclohexan-1,3- diyl; cyclohexan-1,4- diyl; cyclopentane- 1,1 -diyl; cyclopentan-l,2-diyl; and cyclopentan-l,3-diyl, aryl: selected from homoaromatic compounds having a molecular weight under 300, arylene: selected from the group consisting of: 1 ,2-phenylene; 1,3- phenylene; 1 ,4-phenylene; 1,2- naphtalenylene; 1,3-naphtalenylene; 1,4- naphtalenylene; 2,3-naphtalenylene; l-hydroxy-2,3- phenylene; 1 -hydroxy-2,4- phenylene; l-hydroxy-2,5- phenylene; and l-hydroxy-2,6-phenylene, heteroaryl: selected from the group consisting of: pyridinyl; pyrimidinyl; pyrazinyl; triazolyl; pyridazinyl; 1,3,5-triazinyl; quinolinyl; isoquinolinyl; quinoxalinyl; imidazolyl; pyrazolyl; benzimidazolyl; thiazolyl; oxazolidinyl; pyrrolyl; carbazolyl; indolyl; and isoindolyl, wherein the heteroaryl may be connected to the compound via any atom in the ring of the selected heteroaryl,

Unless otherwise specified the following are more preferred group restrictions that may be applied to groups found within compounds disclosed herein: alkyl: linear and branched Cl-C6-alkyl, alkenyl: C3-C6-alkenyl, cycloalkyl: C6-C8-cycloalkyl, alkoxy: Cl-C4-alkoxy, alkylene: selected from the group consisting of: methylene; 1 ,2-ethylene; 1,3-propylene; butan-2-ol- 1,4-diyl; 1 , 4-butylene; cyclohexane- 1,1 -diyl; cyclohexan-l,2-diyl; cyclohexan-l,4-diyl; cyclopentane- 1 , 1 -diyl; and cyclopentan- 1 ,2-diyl, aryl: selected from group consisting of: phenyl; biphenyl; naphthalenyl; anthracenyl; and phenanthrenyl, arylene: selected from the group consisting of: 1 ,2-phenylene; 1,3- phenylene; 1 ,4-phenylene; 1,2- naphtalenylene; 1 ,4-naphtalenylene; 2,3- naphtalenylene and l-hydroxy-2,6-phenylene, heteroaryl: selected from the group consisting of: pyridinyl; pyrimidinyl; quinolinyl; pyrazolyl; triazolyl; isoquinolinyl; imidazolyl; and oxazolidinyl, wherein the heteroaryl may be connected to the compound via any atom in the ring of the selected heteroaryl, heteroarylene: selected from the group consisting of: pyridin 2,3-diyl; pyridin-2,4-diyl; pyridin-2,6-diyl; pyridin-3,5-diyl; quinolin-2,3-diyl; quinolin-2,4-diyl; isoquinolin-l,3-diyl; isoquinolin-l,4-diyl; pyrazol-3,5-diyl; and imidazole-2,4-diyl.

According to a preferred embodiment of the present invention, the Ruthenium-Phosphine-Complex comprises more than one Phosphine, i.e. that in the coordination sphere of the ruthenium two or more trivalent phosphororganic components are present so that bonds (may it be covalent or coordination bonds) between the ruthenium and the phosphororganic components are formed at least temporarily during the reaction. Especially preferred are Ruthenium-Triphosphine-Complexes.

It should be noted that the present invention is not limited to Ruthenium-Phosphine-Complexes where all phosphines are bound to the Ruthenium. Actually in many applications of the present invention, the phosphine is used in excess so that also non-bound phosphines are present.

According to a preferred embodiment of the present invention, the Ruthenium-Phosphine-Complex comprises a bisphosphororganic component, trisphosphororganic component or a higher phosphororganic component. The term "bisphosphororganic component" and "trisphosphororganic component" in this context especially means and/or includes organic components in which two and three, respectively, trivalent phosphors are present. It should be noted that not necessarily all of the phosphines are bound to the Ruthenium during step a). Especially if higher phosphororganic components (in the sense of the present invention organic compounds with more than three trivalent phosphors) are used, not all of the phosphors are catalytically involved in the reaction; nevertheless these compounds are preferred compounds within the present invention as well. Especially preferred in this context are phosphororganic components where the "bridging" moiety between the phosphors is an alkyl or alkylene moiety whereas the further ligands at the phosphor are aryl or heteroaryl. An especially preferred component in this context is Triphos = 1,1,1- tris(diphenylphosphinomethyl)ethane, which has the following structure:

According to a preferred embodiment of the present invention, the Ruthenium-Phosphine-Complex comprises a bisphosphororganic component, trisphosphororganic component or a higher phosphororganic component which furthermore includes one or more donor moieties which can serve as ligands for the Ruthenium. Especially preferred in this context are carbenes, nitrogen containing- ligands such as amines or amides, sulfides, phosphites, phosphoamidites, phosphoric ethers or esters. These compounds have proven themselves in practice. Yet especially preferred are bisphosphororganic components with one further donor moiety.

It should be noticed that according to one preferred embodiment of the present invention, the Ruthenium-Phosphine-complex may (prior to the reaction) comprise one or more "volatile" or easy removable ligand which stabilizes the complex so that it may be handled before the reaction but during the reaction sequence is replaced by the reactants. Suitable ligands are i.e. trimethylmethane, cyclopentadienyl, allyl, methylallyl, ethylene, cyclooctadiene, acetylactonate, acetate or carbon monoxide. According to a preferred embodiment of the present invention, step a) is performed under acidic conditions whereby the (initial) concentration of acid is >0.5 times the concentration of Ruthenium (in mol:mol). It has been found that by doing so the reaction speed and the TON can be increased for many applications within the present invention. More preferred the concentration of acid is >0.8 to <20 times the concentration of Ruthenium (in mol:mol), yet more preferred >1 to <10 times. According to a preferred embodiment of the present invention, step a) is performed under acidic conditions whereby the acid is selected out of the group comprising organic or inorganic acids, especially sulfonic acids, especially methanesulfonic acid, trifluormethansulfonic acid, p- toluolsulfonic acid, p-bromobenzosulfonic acid, p-nitrobenzosulfonic acid, sulfuric acid, hydrochloric acid, hydrofluoric acid, trifluoracetic acid, perchloric acid or mixtures thereof. Even more preferred are acids which provide weak coordinating anions after deprotonation, such as bis(trifluoromethane)sulfonimide or mixtures thereof with aforementioned acids. These compounds have proven themselves in practice.

According to a preferred embodiment of the present invention, step a) is carried out at a temperature of >0°C to <200°C, preferably >20°C to <190°C, more preferred >60°C to <180°C, even more preferred >100°C to <170°C and most preferred at >120°C to <160°C. This has been shown to be most efficient for most applications within the present invention. According to a preferred embodiment of the present invention, step a) is carried out in a dipolar protic or aprotic solvent or in CO ₂ (either liquid or near or supercritical). Preferred solvents are ethers, cyclic ethers (such as THF or dioxane) and CO ₂ .

According to a preferred embodiment of the present invention, step a) is carried out at an initial H ₂ pressure of >1 bar, preferably >10 bar, yet preferred >20 bar, most preferred >60 bar . This has been shown to greatly increase the reaction speed and efficiency for most applications of the present invention.

According to a preferred embodiment of the present invention, step a) is carried out at an initial CO ₂ pressure of >1 bar, preferably >10 bar, yet preferred >20 bar. This has been shown to greatly increase the reaction speed and efficiency for most applications of the present invention.

In case that the nitrogen-containing organic compound is an amide, it is especially preferred that step a) is carried out at an initial CO ₂ pressure of >30 bar, yet preferred >40 bar. It has been observed that under these conditions the side-reaction of decarbonylation (which may occur with some amides) can be suppressed or greatly reduced. According to a preferred embodiment of the present invention, the initial pressure ratio of H ₂ : CO ₂ is >0.5: 1 to <5: 1, more preferably >1 :1 to <4:1 and most preferred >1.5: 1 to <3:1. This has been shown to greatly increase the reaction speed and efficiency for most applications of the present invention.

According to a preferred embodiment of the present invention, the method furthermore comprises a step aO) to be performed before step a): aO) Reacting suitable precursor compounds to form the Ruthenium-Phosphine-Complex

Suitable Ruthenium-containing precursor compounds include Ru(acac)3, [Ru(cod)(methylallyl) ₂ ] Ru(nbd)(methylallyl) ₂ , Ru(ethylene)2(methylallyl) ₂ .

Step aO) may be carried out at room temperature or at the same temperature at step a). The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations. Additional details, characteristics and advantages of the object of the invention are disclosed in the subclaims and the following description of the respective Examples which are for illustration of the invention only and non-binding.

Examples Synthesis of [Ru(Triphos)(TMM)]

A 35 mL schlenk tube was charged with 159.5 mg (0.5 mmol) [Ru(cod)(methylallyl) ₂ ] and 312.0 mg 1,1,1 -tris(diphenylphosphinomethyl)ethane (Triphos) in 25 mL toluene. After heating for 2 h at 110 °C, the resulting solution was concentrated in vacuo and treated with 10 mL of pentane. The precipitating complex was isolated and washed three times with 10 mL pentane. After drying, [Ru(Triphos)(TMM)] was obtained as a bright yellow powder in 75 % yield. General procedures for direct methylation of amines with CO ₂ /H ₂ .

All high pressure batch experiments were conducted in stainless steel 10 mL autoclaves equipped with a glass inlet and a magnetic stir bar. Prior to use, the autoclave was dried under vacuum for 3 hours and repeatedly filled with argon. Under an argon atmosphere, catalyst [Ru(Triphos)(TMM)] (0.019 g, 0.025 mmol) and HNTf ₂ (0.014 g, 0.05 mmol) were weighed in a Schlenk tube. After dissolving in THF (1.0 mL), the mixture was transferred via cannula to the autoclave followed by the addition of the aniline substrate (1.0 mmol) in THF (1.0 mL). The autoclave was then pressurized with CO ₂ to 20 bar and then H ₂ was added up to a total pressure of 80 bar. The reaction mixture was stirred and heated to 150 °C in an oil bath. After lOh, the autoclave was cooled in an ice bath and then carefully vented. The reaction solution was analyzed by 'H-NMR with internal standard mesitylene and the results confirmed by gas chromatography using dodecane as internal standard.

EXAMPLE I: Methylation of N-methylaniline to N,N-Dimethylaniline The reaction was carried out as described above, except where indicated. The results are shown in the following Table I:

TABLE I

Entry Acid Temp [C°] Time [h] Yield [%]

[mol%]

1 — 140 10 2

2 HNTf ₂ (0.5) 140 22 11

3 HNTf, (2.5) 140 22 84

4 HNTf, (5), no catalyst added 140 22 0

5 HNTf ₂ (5), 1% catalyst used 140 10 50

6 HNTf ₂ (5) 140 22 97

7 HNTf ₂ (5), 140 22 25

C0 ₂ /H ₂ : (10/30 bar)

8 HNTf, (5) 120 22 81

9 HNTf, (5) 100 22 58

10 HNTf, (5) 150 0.5 9

11 HNTf, (5) 150 1 20

12 HNTf, (5) 150 1.5 29

13 HNTf, (5) 150 2 34

14 HNTf, (5) 150 3 49

15 HNTf, (5) 150 4 69

16 HNTf, (5) 150 8 97

17 HNTf, (5) 150 10 99

18 MSA (5) 150 10 95

19 / TsOH (5) 150 10 97

EXAMPLE II: Methylation of various secondary amines

The following amides were reacted as described above, using the following conditions: Substituted aromatic amine (1.0 mmol), [Ru(Triphos)(TMM)] (2.5 mol%), HNTf, (5 mol%), THF (2 mL), C0 ₂ /H ₂ (20/60 bar), 150 ^° C. Results are shown in the following Table II:

TABLE II

Entry Amine Product Time [h] Yield [%]

EXAMPLE III: Methylation of various primary amines and amides

Several primary amines and Acetanilide were reacted using the following conditions: Substituted primary aniline or amide (1.0 mmol), [Ru(Triphos)(TMM)] (2.5 mol%), HNTf ₂ (5 mol%), THF (2 mL), C0 ₂ /H ₂ (20/60 bar), 150 °C. The results are shown in the following Table III

TABLE III

EXAMPLE IV: Reductive methylation of various imines Several imines were reacted using the following conditions: Substituted imine (1.0 mmol), [Ru(Triphos)(TMM)] (2.5 mol%), HNTf ₂ (5 mol%), THF (2 mL), C0 ₂ /H ₂ (20/60 bar), 100 °C. The results are shown in the following Table IV

TABLE IV

The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.