Field of the invention

The present invention refers to the area of organic synthesis and concerns certain transition metal-ligand complexes, a process for their manufacture, heterogeneous catalysts comprising said complexes and their use in specific organic reactions.

Background of the invention

Transition metal complexes are indispensable in homogeneous catalysis. The central metal atom is complexed by ligands, which can strongly influence selectivity and conversion. In order to achieve a better separation, in some processes the homogeneous transition metal complex is modified by adding special, mostly water-soluble ligands and converted into an aqueous phase.

Homogeneous catalysts have also reached the large-scale industry in recent decades: In a process variant of hydroformylation, for example, the Ruhrchemie Rhone-Poulenc process, reaction is mediated by a rhodium- triphenylphosphane trisulfonate complex (“TPPTS”). Due to the sulfonated ligand, the catalyst remains in the aqueous phase, while the product of the process, n-butanal produced from propene, hydrogen and carbon monoxide, forms an organic phase.

There are countless examples in the state of the art where transition metals such as palladium, platinum or rhodium are combined with sulfonate phosphane ligands. For example, the zwitterionic ligand 3-(di-tert- butylphosphino)propane-1 -sulfonate ("DTBPPS") is used in many palladium-catalyzed reactions, such as Suzuki coupling or Suzuki-Miyaura reaction for the synthesis of biphenyls or biphenyl derivatives by forming a C-C bond. Another example is the Sonogashira reaction for coupling of terminal alkynes with aryl or vinyl halides under palladium-copper catalysis and using an amine as base.

Basically, the catalytic active species is formed prior to the reaction by mixing a suitable transition metal precursor and DTBPPS in water or mixtures of water with organic solvents. The transition metal-ligand complex is prepared in-situ and directly added to the reaction mixture.

Prior art

The use of 3-(di-tert-butylphosphino)propane-1 -sulfonate (DTBPPS) in catalysts, for example for the preparation of imidazo[4,5-C]quinoline-2-one compounds for cancer therapy, is known from the publications WO 2017 076895 A1, WO 2017 153578 A1 and WO 2018 167203 A1 (ASTRA ZENECA). The catalyst is prepared in-situ and added directly to the reaction mixture as a solution.

Object of the invention

In-situ formation or pre-formation of many transition metal-ligand catalysts always means working with a less defined catalytic system and adds complexity to the reaction process, particularly when it comes down to industrial scale production. An isolation of said catalysts by a simple and scalable process in benchtop-stable solid form would be highly desirous, since it would allow adding precisely the required amount of the catalyst to the targeted reaction mixture, both in lab as well on plant-scale, and saves a separate process step for generating the catalyst in-situ. Therefore, it has been the object of the present invention providing defined transition metal-ligand catalysts in stable crystalline form and a simple and scalable process for their manufacture.

Brief description of the figures

Fig. 1: Calculated powdered X-ray diffraction pattern for [Pd(DTBPPS)Cl2]2 prepared in Example 1.

Fig. 2: 3D plot according to the X-ray structure solution for [Pd(DTBPPS)Cl2]2 prepared as disodium salt in Example 1.

Fig. 3a and 3b: 3D plots (different perspectives) according to the X-ray structure solution for [Pd(DTBPPS)Cl2]2 prepared as disodium salt in Example 1 .

Brief description of the invention

A first object of the present invention refers to a solid transition metal-ligand complex of formula (I) in which M1 and M2 individually stand for a transition metal selected from the group consisting of palladium, platinum, rhodium, and iridium;

Hal represents chlorine, bromine or iodine;

R1 , R2, R3 and R4 individually stand for linear or branched alkyl groups having 1 to 12 and preferably 2 to 10 and more preferably 3 to 6 carbon atoms, or cycloalkyl or aryl groups having 3 to 12 and preferably 5 to 12 and most preferably 6 to 10 carbon atoms, including phenyl, adamantyl and norbornyl groups; and L1 and L2 individually stand for a -(A)-(Z) group in which A represents a linear or branched alkylene group having 1 to 6 carbon atoms and Z stands for a -SO3H group or its alkaline or alkaline- earth salt.

The complexes may include 1 , 2, 3, 4, 5 or more molecules hydrate water.

In a preferred embodiment, the complex is represented by the following solid transition metal-ligand complex of formula (II):

Another object of the present invention refers to a method for manufacturing the solid transition metal-ligand complexes of formula (I) or (II) comprising or consisting of the following steps: (a) providing a transition metal halide according to formula (Illa) to (Hid) or a mixture thereof:

M1 (Hal) ₂ M2(Hal) ₂ [M1(Hal) ₄ ]M* [M2(Hal) ₄ ]M*

(Illa) (lllb) (lllc) (Hid)

(b) providing an aqueous solution of a ligand according to formula (IVa) or (IVb) or a mixture thereof:

L1 PR1 R2 L2PR3R4

(IVa) (IVb) wherein M1 , M2, Hal, L1 , L2, R1 , R2, R3 and R4 have the abovedefined meanings, and M* stands for an alkali metal (preferably Li, Na, K, Rb, Cs) or ammonium;

(c) blending the ligand solution of step (b) with the transition metal halide of step (a) to form a suspension;

(d) adding a source of alkali to said suspension to precipitate the transition metal-ligand complex; and

(e) separating the crystals thus obtained from the aqueous phase.

Surprisingly, it has been observed, that adding a source of alkali to the reaction mixture of transition metal halide and ligand leads to a quick and almost complete precipitation of the complexes in form of solid and stable crystals, which can be easily separated off from the aqueous phase, dried and stored.

Reaction materials

In a fist embodiment said transition metal halides can be selected from the group consisting of:

- palladium (II) chloride, palladium (II) bromide, palladium (II) iodide,

- platinum (II) chloride, platinum (II) bromide, platinum (II) iodide,

- rhodium (HI) chloride, rhodium (HI) bromide, rhodium (HI) iodide,

- iridium (HI) chloride, iridium (HI) bromide, iridium (HI) iodide,

- sodium tetrachloropalladate(ll), sodium tetrabromopalladate(ll), - sodium tetrachloroplatinate(ll), sodium tetrabromoplatinate(ll), and mixtures thereof. The preferred halide is palladium dichloride.

In a second preferred embodiment said ligands can be selected from the group consisting of:

- (dimethylphosphino)methane sulfonic acid;

- (diethylphosphino)methane sulfonic acid;

- (dipropylphosphino)methane sulfonic acid;

- (di-n-butylphosphino)methane sulfonic acid;

- (di-cyclohexylphosphino)methane sulfonic acid;

- (di-phenylphosphino)methane sulfonic acid;

- (di-adamantylphosphino)methane sulfonic acid;

- (di-tert-butylphosphino)methane sulfonic acid;

- 2-(dimethylphosphino)ethane-1 -sulfonic acid;

- 2-(diethylphosphino)ethane-1 -sulfonic acid;

- 2-(dipropylphosphino)ethane-1 -sulfonic acid;

- 2-(di-n-butylphosphino)ethane-1 -sulfonic acid;

- 2-(di-cyclohexylphosphino)ethane-1 -sulfonic acid;

- 2-(di-phenylphosphino)ethane-1 -sulfonic acid;

- 2-(di-adamantylphosphino)ethane-1 -sulfonic acid;

- 2-(di-tert-butylphosphino)ethane-1 -sulfonic acid;

- 3-(dimethylphosphino)propane-1 -sulfonic acid;

- 3-(diethylphosphino)propane-1 -sulfonic acid;

- 3-(dipropylphosphino)propane-1 -sulfonic acid;

- 3-(di-n-butylphosphino)propane-1 -sulfonic acid;

- 3-(di-cyclohexylphosphino)propane-1 -sulfonic acid;

- 3-(di-phenylphosphino)propane-1 -sulfonic acid;

- 3-(di-adamantylphosphino)propane-1 -sulfonic acid;

- 3-(di-tert-butylphosphino)propane-1 -sulfonic acid;

- 4-(dimethylphosphino)butane-1 -sulfonic acid;

- 4-(diethylphosphino)butane-1 -sulfonic acid;

- 4-(dipropylphosphino)butane-1 -sulfonic acid; - 4-(di-n-butylphosphino)butane-1 -sulfonic acid;

- 4-(di-cyclohexylphosphino)butane-1 -sulfonic acid;

- 4-(di-phenylphosphino)butane-1 -sulfonic acid;

- 4-(di-adamantylphosphino)butane-1 -sulfonic acid;

- 4-(di-tert-butylphosphino)butane-1 -sulfonic acid; or their alkaline and/or alkaline earth salts; and mixtures of said sulfonic acids and/or sulfonates. The preferred ligand is 3-(di-tert- butylphosphino)propane-1 -sulfonic acid or its sodium salt.

In a third preferred embodiment said source of alkali can be an aqueous solution of an alkali hydroxide, an alkali carbonate or alkali hydrogen carbonate. Suitable examples encompass aqueous solutions of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, and mixtures thereof. Particularly preferred is, however, an aqueous solution of sodium hydrogen carbonate, since this source of alkali, particularly when added dropwise, generates only little gas in small bubbles and supports a fast and complete precipitation.

Overall preferred is a method involving palladium (II) chloride as the halide, 3-(di-tert-butylphosphino)propane-1 -sulfonic acid as the ligand and an aqueous solution of sodium hydrogen carbonate as the source of alkali. In certain cases a further addition of sodium halides, preferably sodium chloride in amounts of up to equivalent per equivalent halide can also be useful to support solubility. It has been found useful adding the source of alkali in amounts of about 80 to about 120 mol-percent, preferably about 90 to about 100 mol-percent calculated on the amount of transition metal halide. Particularly preferred is using a mixture of PdCl2 and NaCI forming a [PdCl4]Na2 complex, which shows improved solubility compared to palladium chloride taken alone.

Typically, the reaction is conducted at a temperature of from about 30 to about 80 °C, and preferably at about 50 °C. Subsequently, the precipitated crystals are preferably cooled to about 0 °C, separated off from the aqueous phase by filtration, and dried to constant weight for example in a desiccator. The crystals can be stored for at least 6 weeks in the dark, preferably under inert gas.

Heterogeneous catalysts

Another object of the present invention refers to a heterogeneous catalyst comprising or consisting of:

(a) the homogenous transition metal-ligand complex as explained above and

(b) a support.

Suitable supports can be selected for example from the group consisting of activated charcoal, alumina oxide, silica dioxide, alkaline or alkaline earth silicates or mixtures thereof. The loading can range from about 0.1 to about 5 wt. -percent, preferably from about 0.5 to about 2 wt. -percent.

Another object of the present invention encompasses a method for manufacturing said heterogeneous catalysts comprising or consisting of the following steps:

(i) providing an aqueous suspension of the solid transition metal-ligand complex as explained above;

(ii) providing a support;

(iii) bringing the aqueous solution of step (i) into contact with the support of step(ii) and precipitate the solid complex on the surface of the support; and optionally

(iv) drying of the heterogeneous catalyst thus obtained.

In the alternative it is also possible adding the support to the suspension of the halides and the ligand and to precipitate the crystals on the surface of the support by adding said source of alkali. Subsequently the water phase is removed and the loaded support dried and optionally subjected to calcination.

Industrial application

Another object of the present invention refers to the use of the solid transition metal-ligand complexes or the heterogeneous catalysts as described above as catalysts, preferably for cross-coupling reactions such as Suzuki couplings and Sonogashira reactions.

The present invention is further illustrated by the examples following hereinafter which shall in no way be construed as limiting. The skilled person will acknowledge that various modifications, additions and alternations may be made to the invention without departing from the spirit and scope of the invention.

Working Examples

Example 1

Manufacture of solid [Pd(DTBPPS)Cl2]2

A solution of 3-(di-tert-butylphosphonium)propane-1 -sulfonate (153 g, 564 mmol = 1 .0 equiv.) in purified water (402 ml) was added to a solid mixture of palladium(ll)chloride (100g, 564 mmol, 1.0 equiv.) and sodium chloride (33 g, 564 mmol = 1 .0 equiv.). The resulting suspension was stirred at 50 °C for one hour and a clear solution was formed). To this reaction mixture a solution of sodium hydrogen carbonate (47.4 g, 564 mmol, and 1 .0 equiv.) in purified water (300 ml) was added slowly under dose-controlled gas evolution and a suspension of golden-red crystals was obtained. The reaction mixture was cooled to 0 °C, submitted to a filtration step and the crystals thus obtained dried by vacuum. The total yield was 243 g equivalent to 289 mmol and about 91 % of theory.

The crystals were subjected to a X-ray single crystal analysis which revealed the structure being a disodium salt of a Pd-dimer including 3 moles hydrate water according to the following structure: with the sum formula [Pd(DTBPPS)Cl2]2. Figure 1 shows the respective calculated powder X-ray diffraction pattern, and Figures 2, 3a and 3b show 3 D plots from different perspectives according to the X-ray structure solution.

Comparative Example C1

Manufacture of [Pd(DTBPPS)Cl2]2 in solution

The comparative example was conducted according to WO 2018 167203 A1 . Degassed water (30 mL) was added to sodium tetrachloropalladate(ll) (0.41 g, 1.39 mmol) and 3-(di-tert-butylphosphino)propane-1 -sulfonic acid (0.75 g, 2.79 mmol) at ambient temperature under an inert atmosphere. The suspension was stirred for 5 minutes, then the solid removed by filtration and discarded to leave the desired reagent as a red-brownish solution, which was ready for subsequent addition as a catalyst to a reaction mixture

Kinetic Examples

The following examples were made for comparing the activities of the solid catalyst according to the present invention (Example 1 ) and the in-situ catalyst according to the state of the art (Comparative Example C1 ). Both catalysts were tested in an aqueous phase Suzuki coupling of aryl bromides [see W.S. BROWN et al. in SYNTHESIS, 12, p 1965-1970 (2008)]. The results are shown in Table 1 .

Example 2

Solid [Pd(DTBPPS)Cl2]2 according to invention

[Pd(DTBPPS)CI ₂ ] ₂ (28.4 mg, 0.03 mmol 1.0 mol%) of Example 1 , Na ₂ CO ₃ (350 mg, 3.3 mmol 110 mol%), 4-cyanophenylboronic acid (570 mg, 3.9 mmol, 1 .3 equiv.) and 4-bromoanisole (560 mg, 3.0 mmol, 1 .0 equiv.) were charged into a dry 10 mL vial. The vial was flushed with N ₂ and sealed with a septum. Purified water (6 ml) and MeCN (6 ml) were added and the vial was stirred at 45°C, the biphasic reaction mixture was monitored by HPLC.

Comparative Example C2

DTBPPS/Pd in-situ

PdCI ₂ (10.6 mg, 0.06 mmol, 2.0 mol%), DTBPPS (16,3 mg, 0,06 mmol, 2.0 mol%), NaCI (3.5 mg, 0.06 mmol, 2.0 mol%), Na ₂ CO3 (350 mg, 3.3 mmol, 1.1 equiv.), 4-cyanophenylboronic acid (570 mg, 3.9 mmol, 1.3 equiv.) and 4-bromoanisole (560 mg, 3.0 mmol, 1.0 equiv.) were charged into a dry 10 mL vial. The vial was flushed with N ₂ and sealed with a septum. Purified water (6 ml) and MeCN (6 ml) were added and the vial was stirred at 45°C, the biphasic reaction mixture was monitored by HPLC.

Table 1 : Results of kinetic measurements.

The results clearly show that the solid catalyst according to the present invention leads to the same yields compared to the in-situ catalyst according to the state of the art, however, conversion is much faster.