Patent Description:
In the classical and industrially carried out vinylation of N-H compounds with acetylene, usually strong alkaline bases were used as the catalyst (see: <NPL> and <NPL>). Frequently the alkaline base catalyst needs to be prepared in a separate process step just before the reaction ("base preparation"). A drawback of this state-of-the-art approach are the harsh and strongly basic conditions, which are leading to reduced yields especially when base-sensitive substrates like cyclic carbamates or lactams are used to produce the corresponding N-vinyl compounds.

To overcome these intrinsic drawbacks and run the vinylation under milder conditions, different approaches were reported, to use more efficient catalysts which can facilitate the N-vinylation with acetylene under milder conditions.

From <CIT> it is known to produce vinyl compounds by reacting acetylene with a Brønsted acid in presence of a heterogeneous, supported catalyst comprising ruthenium.

<CIT> discloses a homogeneously catalyzed reaction of acetylene with ammonia or a primary or secondary amino compound at <NUM> to <NUM> bars; <NUM> bars are used in the examples. Various catalysts are disclosed, inter alia catalysts based on ruthenium are mentioned.

<NPL> discloses homogeneously catalyzed N-vinylation of cyclic amides and related cyclic compounds using a Ruthenium catalyst with phosphine ligands under low acetylene pressures of <NUM> bar.

A drawback of the afore mentioned systems is the use of the expensive precious metal Ruthenium as the active catalyst. To overcome this drawback, precious metal-free catalyst systems working under mild reaction conditions (e.g. less basic or acidic) would be beneficial.

<NPL> describes the use of phosphines as catalysts in the addition of internal and external alkynoates to activated NH-compounds as phthalimides and sulfonamides to the corresponding N-vinyl-compounds using phosphines as catalysts. A drawback of this system is, that large amounts (more than <NUM> mol%) of acidic co-catalysts as Acetic Acid or phenol are required. Also, it could not be shown, that this catalytic system works for the vinylation of less acidic NH-compounds with simple acetylene as the alkyne.

As acetylene is gaseous, reactions with acetylene are usually performed under pressure. It is desirable from the economical as well as reaction safety point of view to keep the pressure as low as possible.

It was an object of this invention to provide a process for the synthesis of N-vinyl compounds, which can be performed at low pressure, under less basic or acidic conditions and without the need for base preparation as described in the state-of-the-art and wherein the N-vinyl compounds are obtained in high yield and selectivity.

Accordingly, a process to produce N-vinyl compounds by homogeneous catalysis has been found, wherein acetylene is reacted with a compound having at least one nitrogen bearing a substitutable hydrogen residue in a liquid phase in the presence of.

The N-H-compound is an organic nitrogen containing compound with at least one nitrogen bearing a substitutable hydrogen residue with a pKa determined in Dimethylsulfoxide of this hydrogen in the range of <NUM> to <NUM>. The experimental pKa-values were adapted from literature and measured by the spectrophotometric method in DMSO against indicator at <NUM>, see: <NPL> and <NPL>. The corresponding experimental pKa values were taken from the following references: <NPL>; B. Terekhova, E. Stehlíček, J. Sebenda, Collect. <NUM>, <NUM>, <NUM>-<NUM>; <NPL>; <NPL>. For the substrates, where the pKa values where not experimentally available, the corresponding pKa values in DMSO were calculated via DFT calculations according the following method:
All geometry optimizations were carried out at the BP86/def2-SV(P)<NUM> level of theory. Stationary points were verified via analysis of the vibrational frequencies at the level of geometry optimization. Final electronic energies were obtained by single-point calculations at the PBE0-D3(BJ)/def2-QZVPP<NUM> level of theory employing Grimme's D3 dispersion correction<NUM> incorporating Becke-Johnson damping. <NUM> All quantum-chemical calculations were carried out using the TURBOMOLE program<NUM> (Version <NUM>) with the resolution-of-identity (RI) approximation<NUM> and the corresponding auxiliary basis sets<NUM> implemented in the program. Zero-point vibrational energies and thermodynamic corrections were obtained at the level of geometry optimization (T = <NUM> and p = <NUM> bar). Solvent corrections to Gibbs free energies in DMF were calculated for all species with the conductor-like screen model for real solvents (COSMO-RS)<NUM> carried out with the COSMOtherm program<NUM> (Version <NUM>. <NUM>; Revision <NUM>). All pKas were calculated using a proton exchange scheme with referencing to either <NUM>-Pyrrolidone or <NUM>-Oxazolidinone, which have been extensively used before e.g. by Ho et al. <NUM> <MAT> <MAT>.

Refences for the pKa-calcaultions: [<NUM>] (a) <NPL>; (b) <NPL>; (c) <NPL>. [<NUM>] <NPL>; (b) <NPL>; (c) <NPL>. [<NUM>] <NPL>. [<NUM>] <NPL>. [<NUM>] (a) <NPL>; (b)<NPL>; (c) <NPL>. [<NUM>] (a) <NPL>; (<NPL>; (c) <NPL>; (d) <NPL>. [<NUM>] (a) <NPL>; (b) <NPL>. [<NUM>] (a) <NPL>; (b) <NPL>. [<NUM>] (a) <NPL>. de; (b) <NPL>. [<NUM>] (a) <NPL>; (b) <NPL>.

In a particularly preferred embodiment, the N-H-compound is a linear amide, a lactam, a cyclic carbamate, a pyrrole, an imidazole, a carbazole, an indol, a triazole, an urea or a diarylamine.

The linear amide comprises an amide group -NH-C(=O)-CR<NUM>-.

The cyclic amide comprises an amide group -NH-C(=O)-CR<NUM>- as element to the ring system.

The cyclic carbamate comprises a carbamate group -NH-C(=O)-O- as element to the ring system.

The imidazole comprises an imidazole unit with an NH-function.

The pyrrole comprises a pyrrole unit with an NH-function.

The Diarylamine comprises a Ar<NUM>NH function.

The Urea comprises a -NRH-C(=O)-NRH-function.

The further carbon atoms of the linear or ring system, the imidazole or the aryl-groups of the diarylmine may be substituted or unsubstituted. Substituents to the carbon atoms may be, for example, carbonyl groups (=O), aliphatic or aromatic hydrocarbon groups that may comprise heteroatoms, notably oxygen in form of ether groups, two neighbored carbon atoms may be part of a further rings system, such as a cycloaliphatic or aromatic ring system.

In the process of the invention, the NH-compound comprising a hydrogen substituted nitrogen is reacted with acetylene in the presence of one phosphine as catalyst, also called vinylation catalyst hereinafter, either a solvent selected from linear ethers, cyclic ethers, linear amides, cyclic amides, sulfoxides, nitriles and halogenated hydrocarbons or without a solvent, and no metal atom or ion binding the phosphine as a ligand.

Suitable phosphines as catalyst for the vinylation of the process according to the invention are, for example, mono-, bi-, tri- and tetra dentate phosphines of the formulae I and II shown below,
<CHM>
where
n is <NUM> or <NUM>;.

A is a bridging group. For the case that A is selected from the group unsubstituted or at least monosubstituted C<NUM>-C<NUM>-alkane, C<NUM>-C<NUM>-cycloalkane, C<NUM>-C<NUM>-heterocycloalkane, C<NUM>-C<NUM>-aromatic and C<NUM>-C<NUM>-heteroaromatic for the case (n = <NUM>), two hydrogen atoms of the bridging group are replaced by bonds to the adjacent substituents Y<NUM> and Y<NUM>. For the case (n = <NUM>), three hydrogen atoms of the bridging group are replaced by three bonds to the adjacent substituents Y<NUM>, Y<NUM> and Y<NUM>.

For the case that A is P (phosphorus), the phosphorus forms for the case (n = <NUM>) two bonds to the adjacent substituents Y<NUM> and Y<NUM> and one bond to a substituent selected from the group consisting of C<NUM>-C<NUM>-alkyl and phenyl. For the case (n = <NUM>), the phosphorus forms three bonds to the adjacent substituents Y<NUM>, Y<NUM> and Y<NUM>.

For the case that A is N (nitrogen), the nitrogen for the case (n = <NUM>) forms two bonds to the adjacent substituents Y<NUM> and Y<NUM> and one bond to a substituent selected from the group consisting of C<NUM>-C<NUM>-alkyl and phenyl. For the case (n = <NUM>), the nitrogen forms three bonds to the adjacent substituents Y<NUM>, Y<NUM> and Y<NUM>.

For the case that A is O (oxygen), n = <NUM>. The oxygen forms two bonds to the adjacent substituents Y<NUM> and Y<NUM>.

In a preferred embodiment, the process according to the invention is carried out in the presence of one phosphine catalyst of the general formula (V),
<CHM>
where.

In a preferred embodiment, the process according to the invention is carried out in the presence of one phosphine catalyst of the formula I, preferred herein are those in which R<NUM>, R<NUM> and R<NUM> are each phenyl or alkyl optionally carrying <NUM> or <NUM> C<NUM>-C<NUM>-alkyl substituents and those in which R<NUM>, R<NUM> and R<NUM> are each C<NUM>-C<NUM>-cycloalkyl or C<NUM>-C<NUM>-alkyl. The groups R<NUM> to R<NUM> may be different or identical. Preferably the groups R<NUM> to R<NUM> are identical and are selected from the substituents mentioned herein, in particular from those indicated as preferred.

Preference is given to a trialkylphosphine as catalyst according compound (I) where R1, R2 and R3 are alkyl groups, especially preferred is a compound (I) where R1, R2 and R3 are the same alkyl groups.

In a preferred embodiment, the trialkylphosphine used as catalyst is tri-n-butyl-phosphine or tri-n-octyl-phosphine.

Within the context of the present invention, C<NUM>-C<NUM>-alkyl is understood as meaning branched, unbranched, saturated and unsaturated groups. Preference is given to alkyl groups having <NUM> to <NUM> carbon atoms (C<NUM>-C<NUM>-alkyl). More preference is given to alkyl groups having <NUM> to <NUM> carbon atoms (C<NUM>-C<NUM>-alkyl).

Examples of unsaturated alkyl groups (alkenyl, alkynyl) are vinyl, allyl, butenyl, ethynyl and propynyl.

The C<NUM>-C<NUM>-alkyl group can be unsubstituted or substituted with one or more substituents selected from the group F, CI, Br, hydroxy (OH), C<NUM>-C<NUM>-alkoxy, C<NUM>-C<NUM>-aryloxy, C<NUM>-C<NUM>-alkylaryloxy, C<NUM>-C<NUM>-heteroaryloxy comprising at least one heteroatom selected from N, O, S, oxo, C<NUM>-C<NUM>-cycloalkyl, phenyl, C<NUM>-C<NUM>-heteroaryl comprising at least one heteroatom selected from N, O, S, C<NUM>-C<NUM>-heterocyclyl comprising at least one heteroatom selected from N, O, S, naphthyl, amino, C<NUM>-C<NUM>-alkylamino, C<NUM>-C<NUM>-arylamino, C<NUM>-C<NUM>-heteroarylamino comprising at least one heteroatom selected from N, O, S, C<NUM>-C<NUM>-dialkylamino, C<NUM>-C<NUM>-diarylamino, C<NUM>-C<NUM>-alkylarylamino, C<NUM>-C<NUM>-acyl, C<NUM>-C<NUM>-acyloxy, NO<NUM>, C<NUM>-C<NUM>-carboxy, carbamoyl, carboxamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, C<NUM>-C<NUM>-alkylthiol, C<NUM>-C<NUM>-arylthiol or C<NUM>-C<NUM>-alkylsulfonyl.

C<NUM>-C<NUM>-cycloalkyl is understood in the present case as meaning saturated, unsaturated monocyclic and polycyclic groups. Examples of C<NUM>-C<NUM>-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl groups can be unsubstituted or substituted with one or more substituents as has been defined above in connection with the group C<NUM>-C<NUM>-alkyl. The reaction according to the invention uses as a catalyst one phosphine and no metal atom or ion binding the phosphine as a ligand.

In the inventive process the amount of vinylation catalyst used based on the NH-compound can be varied in a wide range. Usually, the vinylation catalyst is used in a sub-stoichiometric amount relative to the NH-compound. Typically, the amount of vinylation catalyst is not more than <NUM> mol%, frequently not more than <NUM> mol% and in particular not more than <NUM> mol% or not more than <NUM> mol%, based on the amount of the NH-compound. An amount of vinylation catalyst of from <NUM> to <NUM> mol%, frequently from <NUM> mol% to <NUM> mol% and in particular from <NUM> to <NUM> mol%, based on the amount of the NH-compound is preferably used in the process of the invention.

The reaction of a NH-compound with acetylene can principally be performed according to all processes known to a person skilled in the art which are suitable for the reaction of a NH-compound with acetylene.

The acetylene used for the vinylation reaction can be used in pure form or, if desired, also in the form of mixtures with other, preferably inert gases, such as nitrogen, argon or propane, ethane, methane. The acetylene can also be added pressureless or dissolved in an appropriate solvent as dimethylacetamide, dimethylformamide, NMP, or other solvent, suitable to dissolve sufficient amount of acetylene.

The acetylene can be applied discontinuously or continuously, e.g. by bubbling acetylene gas through the reaction mixture or into the reactor or continuous feeding of acetylene into the reactor either as a reactant or dissolved in a solvent.

The reaction is typically carried at an acetylene pressure in the range from <NUM> to <NUM> bar, preferably in the range from <NUM> to <NUM> bar, more preferably in the range from <NUM> to <NUM> bar cold pressure.

In one embodiment of the present invention, the inventive process is characterized in that the reaction between a NH-compound and acetylene is performed at a pressure in the range from <NUM> to 20bar.

The reaction can principally be performed continuously, semi-continuously or discontinuously. The vinylation reaction according to the invention is carried out in a liquid phase. This can be achieved by adding one or more solvents, from the group of linear as well as cyclic ethers, linear as well as cyclic amides, sulfoxides, nitriles and halogenated hydrocarbons. Preferred solvents are DMF, Dimethylacetamide and Diglyme. The liquid phase can also be formed by the NH-compound without any additional solvent.

The reaction can principally be performed in all reactors known to a person skilled in the art for this type of reaction. Suitable reactors are described and reviewed in the relevant prior art e.g. <NPL>".

The inventive process can be performed in a wide temperature range. Preferably the reaction is performed at a temperature in the range from <NUM> to <NUM>, more preferably in the range from <NUM> to <NUM>, in particular in the range from <NUM> to <NUM>.

Inside a Glove Box (Ar), an ACE-Tube (<NUM> volume, thick-walled glass tube with Teflon screwcap, sealed with a teflon O-ring) was charged with substrate (usually: Pyrrolidinone, <NUM>, <NUM> mmol, <NUM> equiv. ) and phosphine catalyst (usually: Tributylphosphine, <NUM>, <NUM> mmol, <NUM> mol%). A Teflon coated magnetic stirring bar was added and the tube was filled with a freshly prepared solution of acetylene in dimethyl acetamide (DMAA) (<NUM>, ca. <NUM> wt, ca. <NUM> mmol, ca. <NUM> equiv. ), prepared by bubbling solvent-free and dried acetylene through absolute DMAA, or with a freshly prepared solution of acetylene in dimethyl formamide (DMF) (<NUM>, ca. <NUM> wt, ca. <NUM> mmol, ca. <NUM> equiv. ), prepared by bubbling solvent-free and dried acetylene through absolute DMF (concentration of substrate: <NUM>). The tube was then sealed and heated by a metal heating block for <NUM> at <NUM>, <NUM> or <NUM>. The tube was then cooled to room temperature and mesitylene (<NUM>µL) was added as an internal GC standard. The reaction mixture was then filtered through a syringe filter and analyzed by calibrated GC or by GC in combination with <NUM>H-NMR.

Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-<NUM> capillary column (<NUM>*<NUM>, <NUM>) with Helium as carrier gas.

GC method: Split: <NUM>/<NUM>, <NUM>/min, const. pressure, <NUM>-<NUM>-<NUM>/min-<NUM>-<NUM>. NMR analysis was done on a Magritek Spinsolve <NUM> Phosphorus Ultra NMR spectrometer with an <NUM>H frequency of <NUM>. The samples were measured in non-deuterated DMAA as a solvent. Proton spectra were achieved with <NUM> scans, <NUM> sek acquisition time per scan, <NUM> sek repetition time and a pulse angle of <NUM> °. Conversion to the viny compound was detected by the three characteristic proton resonances of the vinyl group.

Characteristic example (given in ppm):
<NUM>H-NMR (<NUM>, DMAA) δ = <NUM> (dd, <NUM>JHH = <NUM>, <NUM>JHH = <NUM>, <NUM>, NCH), <NUM> (d, <NUM>JHH = <NUM>, <NUM>, NCHCH<NUM>), <NUM> (d, <NUM>JHH = <NUM>, <NUM>, NCHCH<NUM>).

Inside a Glove Box (Ar), a J. Young NMR tube was charged with a solution of substrate (<NUM> mmol, <NUM> equiv. ) and tributylphosphine (<NUM>, <NUM>µmol, <NUM> mol%) in absolute dimethyl acetamide (DMAA) (<NUM>µL, <NUM>). The tube was sealed with a septum cap and solvent-free and dried acetylene was bubbled through via steel cannula. The septum cap was then replaced inside the Glove Box with a J. Then, the NMR tube was heated to <NUM> by a metal heating block for <NUM> and subsequently analyzed by NMR spectroscopy (<NUM>H and <NUM>P). This process was repeated for <NUM>, <NUM>, <NUM> and once more for <NUM>.

NMR analysis was done on a Magritek Spinsolve <NUM> Phosphorus Ultra NMR spectrometer with an <NUM>H frequency of <NUM>. The samples were measured in non-deuterated DMAA as a solvent. Proton spectra were achieved with <NUM> scans, <NUM> sek acquisition time per scan, <NUM> sek repetition time and a pulse angle of <NUM> °. Conversion to the viny compound was detected by the three characteristic proton resonances of the vinyl group.

Characteristic example (given in ppm):
<NUM>H-NMR (<NUM>, DMAA) δ = <NUM> (dd, <NUM>JHH = <NUM>, <NUM>JHH = <NUM>, <NUM>, NCH), <NUM> (d, <NUM>JHH = <NUM>, <NUM>, NCHCH<NUM>), <NUM> (d, <NUM>JHH = <NUM>, <NUM>, NCHCH<NUM>). <CHM>
ACE-Tube, Analysis by calibrated GC.

<CHM>
ACE-Tube, Analysis by calibrated GC.

Not-isolated yields are usually calculated by addition of GC- resp. NMR-integrals of starting material and product and normalizing the corresponding integrals by this value. Overlapping GC-signals are integrated as automatically done by the ChemStation software, which usually leads to a slight bias towards product formation (underlying broader signal of starting material).

Inside a Glove Box (Ar), a crimp vial (glass, <NUM> volume) was charged with substrate (usually: Pyrrolidinone, <NUM>, <NUM> mmol, <NUM> equiv. ) and phosphine catalyst (usually: Tributylphosphine, <NUM>, <NUM> mmol) was added. If necessary, dimethyl acetamide (DMAA) was added (<NUM> or <NUM>, <NUM> mmol or <NUM> mmol, <NUM> equiv. or <NUM> equiv. A Teflon coated magnetic stirring bar was added and the vial was sealed with a septum cap, the septum was punctuated with a stainless steel cannula and placed inside a Premex (tall) stainless steel autoclave (<NUM> volume) with a Kalrez O-ring. The autoclave was then sealed under argon, purged three times with solvent-free and dried acetylene and finally charged with acetylene (<NUM> bar). The autoclave was then heated by a metal heating block for <NUM> at <NUM> - <NUM>. The autoclave was then cooled to room temperature and depressurized via a bubble counter. After opening the autoclave, mesitylene (<NUM>µL) was added to the crimp vial as an internal GC standard and the reaction mixture was diluted with DMAA (<NUM>). The reaction mixture was then filtered through a syringe filter and analyzed by calibrated GC or by GC in combination with <NUM>H-NMR.

GC method: Split: <NUM>/<NUM>, <NUM>/min, const. pressure, <NUM>-<NUM>-<NUM>/min-<NUM>-<NUM>. The measured GC signal areas, unless properly calibrated, are only supposed to be estimates due to overlapping of the starting material and the product. However, distinction between both species was clearly possible and supported by <NUM>H-NMR spectroscopy.

<CHM>
(Premex tall <NUM>), analysis by calibrated GC.

<CHM>
Premex tall <NUM>, analysis by GC
GC Area starting material/product: <NUM>/<NUM>
<CHM>
Premex tall <NUM>, analysis by GC.

<CHM>
(Premex Tall <NUM>), analysis by GC.

A <NUM>-liter autoclave was charged with <NUM> of <NUM>-methyl-<NUM>,<NUM>-oxazolidin-<NUM>-one (MOX, <NUM> mol, <NUM> equiv. ) and <NUM> (<NUM> mol, <NUM> mol%) of trioctylphosphine (<NUM>%, technical grade) under inert atmosphere. The reactor was closed, filled with acetylene to <NUM> bar acetylene pressure, heated to <NUM>° C and then acetylene was passed through at <NUM> norm-liters/hour rate under the pressure of <NUM> bar for a reaction time of <NUM> hours. A norm-liter is one liter of a gas at <NUM> and <NUM> millibar. The composition of the mixture obtained in the reactor after <NUM> hours of reaction was analyzed via gas chromatography and quantitative NMR.

A <NUM>-liter autoclave was charged with <NUM> of <NUM>-pyrrolidinone (<NUM> mol, <NUM> equiv. ) and <NUM> (<NUM> mol, <NUM> mol%) of trioctylphosphine (<NUM>%, technical grade) under inert atmosphere. The reactor was closed, filled with nitrogen to <NUM> bar, heated to <NUM>° C and then filled with acetylene till <NUM> bar pressure in the reactor. The reactor pressure was kept at <NUM> bar by dosing acetylene during the course of the vinylation reaction. After the reaction was finished the reactor was cooled down to room temperature and depressurized. The composition of the mixture obtained in the reactor after <NUM> hours of reaction was analyzed via gas chromatography and quantitative NMR.

Claim 1:
A process to produce N-vinyl compounds by homogeneous catalysis, wherein acetylene is reacted with a compound having at least one nitrogen bearing a substitutable hydrogen residue in a liquid phase in the presence of
- one phosphine as catalyst,
- either a solvent selected from linear ethers, cyclic ethers, linear amides, cyclic amides, sulfoxides, nitriles and halogenated hydrocarbons or without a solvent, and
- no metal atom or ion binding the phosphine as a ligand.