RU2575249C2 - Novel palladium catalyst, method for production thereof and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a complex of tri-[3,5-bis(trifluoromethyl)-phenyl]-phosphine and palladium (0). The method is carried out by reacting a palladium (II) salt with tri-[3,5-bis(trifluoromethyl)-phenyl]-phosphine and palladium (II) is reduced to palladium (0) in the obtained complex salt. The invention also discloses a catalyst and use thereof.

EFFECT: excellent stability of the complex and enabling use as a catalyst in C-C and C-heteroatom coupling reactions, and for hydrogenation.

18 cl, 1 dwg, 12 tbl, 11 ex

Description

The invention relates to a new palladium catalyst, which is a complex of tri- [3,5-bis (fluoromethyl) phenyl] phosphine and palladium (0).

The invention further relates to a method for producing a new catalyst. The invention also relates to the use of a new catalyst in reactions requiring such catalysts, in particular in reactions with the formation of a C — C bond (cross-coupling reactions, such as the Suzuki, Heck, Stille, and other combinations), in reactions with the formation of a C bond a heteroatom (CN, CO, CS, CP, mainly CN) (for example, the Buchwald reaction), as well as in hydrogenation reactions.

Since at present cross-coupling reactions, which are catalyzed by transition metal complexes (most often Pd and Ni complexes), play an exceptional role in the formation of CC bonds and such reactions have led to radical changes in the synthesis pathways, the invention will be discussed below in the first queue in connection with cross-coupling reactions, but without limiting its scope by this method of application.

The general process of cross-coupling reactions can be described as

Where

R and R ′ are organic groups to be bound by a C — C bond,

M represents a failure of the metal component of the catalytic complex,

L represents ligands present in the catalytic complex,

n represents the number of ligands present,

X represents a substituted atom or group (e.g., Cl, Br, I, triflate, mesylate, tosylate), and

M ′ is a metal or group containing a metal corresponding to the type of cross-coupling reaction under consideration (for example, this metal component is boron for the Suzuki-Miyaura combination, copper for the Sonogashira combination, magnesium for the Harash combination, silicon for the Hiyama combination, tin for Stille combinations, zinc for Negishi combinations, etc.).

The general mechanism of cross-coupling reactions is depicted in FIG. one.

However, in aspects of practical application of these methods have some disadvantages, which are especially pronounced in the field of pharmaceutical industry. One of them is that rather large amounts of catalyst are required (1-5 mol.% Relative to the substrate), in addition, metal impurities, the source of which is the catalyst, can usually be removed from the final product only by tedious and expensive methods. The latter is especially true for palladium catalysts, which, in addition, are highly susceptible to decomposition. As an example, when tetrakis (triphenylphosphine) palladium (0) of the formula (II)

which is still a catalyst that is often used on an industrial scale, is stored in air at room temperature, a significant amount of palladium black is separated in a short time, so it is advisable to store it in a refrigerator in an argon atmosphere. Although cross-coupling reactions using a catalyst of formula (II) are carried out in an inert atmosphere, the separation of palladium black is still widespread, which leads not only to a significant loss of catalyst, but also to the introduction of tedious laborious and expensive stages cleaning up.

The aim of this invention was to obtain a new catalyst based on a palladium complex (0), which is significantly more stable than catalysts based on a palladium complex (0), which were used earlier for cross-coupling reactions, and also makes it possible to significantly reduce the amount of catalyst required per 1 mol of substrate. Within the framework of this field, our main goal was to exclude the formation of palladium black, since palladium black formed from Pd (0) complexes is the final state, and decomposition of the catalyst noticeably reduces the total catalytic activity. In addition, uncontrolled decomposition of the catalyst often leads to uncontrolled amounts of P leaching into the product.

It has now been discovered that the catalyst based on the palladium complex (0) according to the invention fully satisfies the above requirements, and also has additional advantages.

Thus, in one aspect, the present invention relates to a palladium complex (0).

This compound is a bright lemon yellow solid with excellent stability: the formation of palladium black was not observed even in samples that were stored in air at room temperature for more than 20 months.

This compound was stored in air at various T values of temperature and humidity. Samples were periodically taken from the stored product and product decomposition was analyzed based on ³¹ P, ¹⁹ F, ¹³ C and ¹ H NMR spectra (nuclear magnetic resonance). The results are shown in the following table.

Period (month) T, ° C Humidity% Color and degree of decomposition of the stored product one 5 gradually changing lemon yellow, no sampling 25 60 lemon yellow; no decomposition was shown by NMR thirty 65 lemon yellow; no decomposition was shown by NMR 40 75 lemon yellow; no decomposition was shown by NMR four 5 gradually changing lemon yellow, no sampling 25 60 lemon yellow; no decomposition was shown by NMR thirty 65 lemon yellow; no decomposition was shown by NMR 40 75 lemon yellow; no decomposition was shown by NMR 7 5 gradually changing lemon yellow, no sampling 25 60 lemon yellow; no decomposition was shown by NMR thirty 65 lemon yellow; no decomposition was shown by NMR 40 75 lemon yellow; no decomposition was shown by NMR 13 5 gradually changing lemon yellow, no sampling 25 60 lemon yellow; no decomposition was shown by NMR thirty 65 lemon yellow; no decomposition was shown by NMR 40 75 lemon yellow; no decomposition was shown by NMR twenty 5 gradually changing lemon yellow, no sampling 25 60 lemon yellow; no decomposition was shown by NMR thirty 65 lemon yellow; no decomposition was shown by NMR 40 75 lemon yellow; no decomposition was shown by NMR

When testing the compound according to the invention, DSC (differential scanning calorimetry) decomposition was observed at 169.5 ° C. in air at atmospheric pressure. When tested in an inert atmosphere, it was found that the melting point of the compound is 220 ° C. Just for comparison, the non-fluorinated catalyst of formula (II) began to decompose at 98 ° C.

The stability tests were carried out on catalysts based on the complex of [tri- [substituted phenyl] phosphine and Pd (0), where two of the three 3,5- (trifluoromethyl) phenyl groups attached to the phosphorus atom in the ligand were retained, and the third the group is substituted by a mono-, di- or trimethoxyphenyl, tri-isopropylphenyl or 2-pyridyl group. None of these compounds could even come close to the compound according to the invention for storage stability. Thus, the excellent storage stability of this compound is a very surprising characteristic that does not occur even in very close structural analogues.

When studying the stability of the catalyst under the conditions of the cross-coupling reaction, it was found that the catalyst is not sensitive to temperature increase; it retains its stability at any temperature below its melting point. Similarly, an increase in pressure did not affect the stability of the catalyst.

When studying the stability of the catalyst according to the invention, the following was discovered.

The catalyst is insoluble in water at industrial temperatures; at the same time, it remains unlimited when stored in water.

The solubility of the catalyst in alcohols at room temperature increases with an increase in the number of carbon atoms in alcohol; however, at the studied temperature ranges of catalytic reactions (110-130 ° C), its stability in alcohols decreases in parallel with an increase in the number of carbon atoms of the alcohol. However, the stability of the catalyst can be improved or even completely restored by adding water to the reaction mixture. In aqueous alcohols, the dissolution of the catalyst begins at a temperature of about 90 ° C and, depending on the alcohol in question, ends at 110-130 ° C, where the catalytic activity reaches its maximum. However, even at temperatures leading to complete dissolution, separation of palladium black was not observed. Sometimes a slight permissible decomposition occurred, indicated by a slight darkening of the color of the reaction mixture (from lemon yellow to tan). Particularly noteworthy is that, even under such conditions, a complete (100%) chemical conversion could be achieved. For comparison: when the compound of formula (II) was used as a catalyst under much milder conditions than those discussed above (atmospheric pressure; boiling point of the reaction mixture), it was impossible to avoid the formation of palladium black, which clearly indicates a significant decomposition of the catalyst.

In order to avoid the use of pressures above atmospheric, which is undesirable in industrial aspects, the catalyst according to the invention was also tested in industrially important polar aprotic and nonpolar aprotic organic solvents (e.g. dimethyl sulfoxide, dimethylformamide, ethyl methyl ketone, methyl isobutyl ketone, N-methylpyrrolidine and tetrahydrofuran) in which the catalyst is completely soluble at lower temperatures. In these solvents, the formation of palladium black was also not observed, although sometimes the color of the reaction mixture became somewhat darker during the catalytic reaction (color changes from lemon yellow to pink, orange, red or brownish were observed). As with the alcohols discussed above, in some of these solvents, a slight decrease in catalyst stability can be significantly stopped by adding water to the reaction mixture.

In the study of the catalytic activity of this compound in cross-coupling reactions, it was found that under the same substrate and ceteris paribus the required amount of new catalyst can be reduced to a fraction of the number of similar known catalysts (from 1-5 mol.% Relative to the substrate to 0.1-0.3 mol% relative to the substrate) without any significant decrease in yield and chemical conversion achieved during the same reaction time. Although the yield and chemical conversion, which are achieved under the same reaction conditions, during a given reaction time decrease when the amount of catalyst is further reduced below this level, this can be sufficiently compensated by an increase in temperature and / or reaction time. As an example: in the reaction of the combination of Suzuki 2-bromopyridine and 2- (4-ethoxy-3-methylphenyl) -1,3,2-dioxaborolan, carried out in 10: 1 vol./about. mixtures of methanol and water, in the presence of K ₂ CO ₃ at 110 ° C under pressure, 100% chemical conversion was achieved within 1 hour using 0.25 mol.% of the catalyst according to the invention. With a decrease in the amount of catalyst to 0.05 mol% (which is 20% of the previous value), the chemical conversion achieved in one hour still remained quite high (81%), and when using only 0.005 mol% of the catalyst (which is 2% of the previous value and 1-5 thousandths of ordinary industrial values) a chemical conversion of 50% could even be achieved in 1 hour.

In most cases, the removal of palladium from the product is not required because, due to the small amount and high stability of the new catalyst, the product does not have palladium or the amount of residual palladium is below the permissible level. If residual palladium should still be removed, costly purification methods [certain Pd (0) binding operations] commonly used for this purpose may be completely omitted. Residual palladium still in the complexes can be removed by simple operations (chromatography; filtration through an inexpensive carbon filter, etc.), commonly used in industry, and as a rule, more than one purification step is not required.

The invention further relates to a method for producing this catalyst.

The catalyst according to the invention can be easily obtained by reacting a palladium (II) salt with tri- [3,5-bis (trifluoromethyl) phenyl] phosphine, preferably with at least a four-fold molar excess of said compound, and reducing palladium (II) to palladium (0) in the resulting complex salt in a one- or multi-stage reaction, preferably carried out in a single reaction vessel without isolation of intermediate compounds. As the palladium (II) salt, palladium dichloride can preferably be used; a preferred reducing agent is hydrazine hydrate.

Tri- [3,5-bis (trifluoromethyl) phenyl] phosphine, used as a complexing agent, is a known substance [see, for example, H. G. Alt, R. Baumgaertner, N.A. Brune: Chemische Berichte 119 (5), 1694-1703 (1986)].

The invention also relates to the use of a compound according to the invention as a catalyst in C-C and C-heteroatom coupling reactions, as well as in hydrogenation.

It was found that the compound according to the invention can be used in any type of these reactions. The conditions of such reactions may be the same as those used with other catalysts based on Pd (0) complexes, with the difference that when using the compounds of the invention as a catalyst, usually smaller, sometimes much smaller amounts of catalyst are still sufficient to carry out the reaction. Based on his general knowledge and on the basis of the information presented in this description, a person skilled in the art can easily determine the optimal parameters for reactions using a catalyst using standard methods or sometimes simple tests and taking into account the dissolution characteristics of the catalyst. It should be noted that the idea of using the catalyst according to the invention, prepared in situ (for example, Pd ₂ (dba) ₃ with PPh ₃ (CF ₃ ) ₆ ), is not feasible, since the uncontrolled complexation and almost instantaneous appearance of Pd-black leads to low outputs.

The following Examples serve to illustrate further details of the invention.

Example 1

Obtaining a catalyst according to the invention

Argon was bubbled through 30 ml of dimethyl sulfoxide at room temperature, and then 6.7 g (0.01 mol) of tri- [3,5-bis (trifluoromethyl) phenyl] phosphine and 0.355 g (0.002 mol) of palladium (II) chloride were added. ) After that, the mixture was heated to 110-130 ° C. After the solution was completely transparent, indicating that the complex had formed, 0.5 g (0.01 mol) of hydrazine hydrate was added to the mixture. Then the flask was immersed in ice water. The separated product was filtered through a porous glass filter and washed three times with chloroform. A solid crystalline solid of bright lemon yellow color was obtained with a yield of 90%.

Characteristic data of the NMR spectrum: ¹ H-NMR (300 MHz, THF-d ₈ (tetrahydrofuran), δ = 3.58 ppm ^-1 ) 8.17 (s, 12H), 7.84 (s, 24H); ¹³ C-NMR (75 MHz, THF-d _8, δ = 67,3 million ^{-1) 138.1 (C), 133.7} (q, J = 38,7 Hz, C), 133.4 (CH) , 126.3 (CH) 123.4 (q, J = 271.57 Hz, CF ₃ ); ³¹ P-NMR (300 MHz, THF-d ₈ ) 28.77; ¹⁹ F-NMR (300 MHz, THF-d ₈ ) -62.94.

Example 2

Obtaining 2- (4-ethoxy-3-methylphenyl) pyridine using the Suzuki coupling reaction using 10/1 vol./about. mixtures of methanol and water as solvent and catalyst according to the invention

General protocol

The amount of catalyst that will be given below, 618 mg (3 mmol) of 2- (4-ethoxy-3-methylphenyl) -1,3,2-dioxaborolan and 553 mg (4 mmol) of potassium carbonate was weighed into a flask. Then the flask was placed in an argon atmosphere and 10 ml of methanol and 1 ml of water were added. At the end, 316 mg (190 μl, 2 mmol) of 2-bromopyridine (substrate) was introduced using an automatic pipette. The flask was closed and the reaction mixture was stirred at a temperature and for the time given below, optionally at a pressure above atmospheric.

For processing purposes, the cooled reaction mixture was extracted four times with 5 ml of chloroform each time; thus, almost the entire amount of catalyst was removed from the product. Since the chloroform extract still contained an dioxoborolan impurity, the substance thus separated was further purified by silica gel column chromatography using 3/1 v / v. a mixture of hexane and ethyl acetate as an eluting agent.

Test Series (A)

In this series of tests, the reactions were carried out at a temperature of 110 ° C and at a pressure above atmospheric for 1 hour. The amount of the compound according to the invention was different, and it was checked how its change affects the achieved chemical conversion.

In all cases presented in this description, the chemical conversion values were determined on the basis of ¹ H NMR spectra or by gas chromatography. The results are presented in Table 1. Despite these rather small-scale test reactions, the processing of the mixture affects the practical yield; these data are also provided for reference.

Table 1 Amount of catalyst Chemical conversion achieved in 1 hour,% Practical yield,% mg mol% relative to the substrate 56 one one hundred 89 28 0.5 one hundred 87 fourteen 0.25 one hundred 88 2.8 * 0.05 81 69 0.28 * 0.005 fifty 39 * The catalyst was added to the mixture as a stock solution prepared with tetrahydrofuran.

No separation of palladium mobile was observed in any case; the color of the reaction mixture remained lemon yellow in all reactions. Particularly noteworthy is that 50% chemical conversion could still be achieved within 1 hour, when the amount of catalyst according to the invention was only 0.005 mol%. According to the experience gained in other tests, this decrease in the efficiency of the chemical transformation can be compensated by an increase in the reaction time and / or reaction temperature.

In tests conducted for verification purposes, the above reaction was repeated so that the catalyst was not added to the reaction mixture. Thus, they intended to make sure that the formation of the product can really be explained by the fact that the catalyst is introduced in a very small amount, and not by the action of any metal impurities that might be present in solvents or in flasks. Under these conditions, the chemical conversion efficiency was zero, thus, it can be stated with full confidence that the catalyst according to the invention is active even in an amount of 0.005 mol%.

Test Series (B)

In this series of tests, 0.25 mol% of the catalyst according to the invention was used for 1 mol of 2-bromopyridine as a substrate and the reaction was carried out for 1 hour at temperatures shown in Table 2, above atmospheric pressure, if necessary. Checked how temperature changes affect the achieved chemical conversion. The results are shown in Table 2; practical outputs are also provided for reference.

table 2 Temperature ° C Temperature ° C Temperature ° C achieved in 1 hour,% 25 0 0 fifty 5 not measured 70 25 16 90 60 47 110 one hundred 88

The observed results show that when applying 10/1 vol./about. mixtures of methanol and water as a reaction medium, it is recommended to carry out the coupling reaction at a temperature above 90 ° C and at a pressure above atmospheric, which allows the reaction mixture to remain in a liquid state. This can be explained by the fact that a remarkable dissolution of the catalyst occurs at such temperatures. The formation of palladium black or any other sign of decomposition of the catalyst could not be observed in any of the reactions. For comparison; when in the reaction that was carried out at a temperature of 110 ° C, the catalyst according to the invention was replaced with the same amount of the catalyst of formula (II), the reaction mixture blackened for several minutes. After completion of the reaction, it is very difficult to remove metallic impurities. The product obtained in this last reaction remained orange-yellow / dark orange-yellow even after the complete removal of palladium black, while using the catalyst according to the invention, a snow-white product was obtained.

The physical constants of all product samples obtained in Example 2, within the measurement accuracy, were in good agreement with each other and with the corresponding parameters of the sample of the authentic product. For reference, the physical constants measured for a sample of 2- (4-ethoxy-3-methoxyphenyl) pyridine prepared in 10/1 v / v are given below. mixtures of methanol and water at 110 ° C for 1 hour using 0.25 mol.% of the catalyst according to the invention:

¹ H NMR (300 MHz, CDCl _3, δ _TMS = 0 million ^{-1): 8.65 (d, J} = 4,8 Hz, 1H), 7.75 (m, 4H), 7.16 (m, 1H), 6.90 (d , J = 8.4 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H), 2.31 (s, 3H), 1.45 (t, J = 7.2 Hz).

¹³ C-NMR (75 MHz, CDCl _3, δ _CDCl3 = 77,00 mn ^{-1): 158.2 (C),} 157.3 (C), 149.3 (CH), 136.7 (CH), 131.1 (C), 129 (CH ), 127.1 (C), 125.5 (CH), 121.2 (CH), 119.9 (CH), 111.0 (CH), 63.6 (CH ₂ ), 16.4 (CH ₃ ), 14.9 (CH ₃ ).

IR (KBr, ν cm ^-1 ): 1604, 1587, 1561, 1467, 1433, 1394, 1309, 1281, 1247, 1181, 1151, 1131, 1109, 1042, 926, 884, 777, 742, 618.

Example 3

Obtaining 2- (4-ethoxy-3-methylphenyl) pyridine using the Suzuki coupling reaction in a reaction medium other than 10/1 v / v. mixtures of methanol and water, and using the compound of the invention as a catalyst

The Suzuki coupling reaction described in Example 2 was repeated using 316 mg (190 μl, 2 mmol) of 2-bromopyridine as a substrate and a total amount of the reaction medium of 11 ml, however, the reaction conditions (composition of the reaction mixture; amount of catalyst; amount of reagent dioxoborolan; reaction time; temperature) varied as shown in Table 3. Chemical conversion was evaluated as described in Example 2. The results are shown in Table 3.

Table 3 Solvent, 10 ml / 1 ml The catalyst, mg / mol.% Time hour Dioxoborolan equivalent Temperature ° C Chemical conversion,% EtOH / H ₂ O 14 / 0.25 one 1,5 110 one hundred iPrOH / H ₂ O 14 / 0.25 one 1,5 110 one hundred tBuOH / H ₂ O 14 / 0.25 one 1,5 110 one hundred Hexane / H ₂ O 14 / 0.25 one 1,5 110 27 DME (dimethoxyethane) / H ₂ O 14 / 0.25 1,5 110 48 THF / H ₂ O 14 / 0.25 one 1,5 110 85 THF / H ₂ O 0.112 / 0.002 19 1,5 110 26 THF / H ₂ O 0.112 / 0.002 72 1,5 110 78 THF / H ₂ O 0.112 / 0.002 one 1,5 130 39 THF / H ₂ O 0.112 / 0.002 3 1,5 130 74 THF / H ₂ O 0.112 / 0.002 19 1,5 130 one hundred THF / H ₂ O 0.112 / 0.002 3 1,1 130 33

When aqueous ethanol, aqueous isopropanol and aqueous tert-butanol were used, with a reaction time of 1 hour, the color of the reaction mixture gradually became more saturated and turned brown; the order of color saturation was as follows: ethanol-isopropanol-tert-butanol. However, palladium black did not separate in any of the examples and the degree of chemical conversion remained 100%, reflecting that the catalyst remained active. When carrying out the reaction in hexane / water, dimethoxyethane / water and tetrahydrofuran / water mixtures, it was found that the quality of the organic solvent as a component of the reaction mixture highly affects the degree of chemical conversion achieved over a given period of time. This is common for cross-coupling reactions. In this case, the formation of palladium black could not be observed with these solvents, although sometimes the color of the reaction mixture became more saturated during the reaction. The test results that were carried out in a tetrahydrofuran / water mixture are particularly noteworthy. The test was also carried out with an extremely small amount of catalyst (0.002 mol%, about one thousandth of the amount required for known catalysts). As in Example 2, this extremely small amount of catalyst was introduced into the mixture as a stock solution in tetrahydrofuran. The data clearly show that a decrease in the degree of chemical conversion can be sufficiently compensated by an increase in the reaction time and / or reaction temperature: by increasing the temperature to 130 ° C and the reaction time to 19 hours, 100% chemical conversion could be achieved even with this extremely small amount of catalyst. After the control test described in Example 2 (reaction without a catalyst), they were again convinced that the formation of the product can be explained solely by the presence of a catalyst, and not by the action of any possible metal impurities that could be present in solvents or in flasks. The excellent stability of the catalyst according to the invention is well illustrated by the fact that no sign of decomposition of the catalyst could be observed even after the reaction was carried out at a temperature of 130 ° C for 19 hours, which is a very stringent condition.

Example 4

Obtaining pyridine derivatives using the Suzuki coupling reaction using a catalyst according to the invention

General protocol

14 mg (0.25 mol% relative to the substrate 2-bromopyridine) catalyst, 3 mmol of dioxaborolan reagent and 553 mg (4 mmol) of potassium carbonate were weighed into a flask. Then the flask was placed in an argon atmosphere and 10 ml of methanol and 1 ml of water were added. At the end, 316 mg (190 μl, 2 mmol) of 2-bromopyridine (substrate) was introduced using an automatic pipette. Then the flask was closed and the reaction mixture was stirred for 1 hour at a temperature of 110 ° C at a pressure necessary to maintain the liquid state of the reaction mixture. Then the reaction mixture was processed as described in Example 2.

The reagents used, the products obtained and their physical constants, as well as practical yields (%) are shown in Table 4.

The physical constants of all the products obtained, within the limits of measurement accuracy, were in good agreement with the corresponding parameters of the samples of the authentic product. The reaction mixtures always maintained a lemon yellow color, even after a reaction time of 16 hours. No evidence of further decomposition of the catalyst was detected.

Example 5

Obtaining indole derivatives using the Suzuki coupling reaction using a catalyst according to the invention

General protocol

14 mg (0.25 mol% relative to the substrate 5-bromoindole) of the catalyst according to the invention, 3 mmol of dioxaborolan reagent, 553 mg (4 mmol) of potassium carbonate and 390 mg (2 mmol) of 5-bromindole were weighed into a flask. Then the flask was placed in an argon atmosphere and 10 ml of methanol and 1 ml of water were added. Then the flask was closed and the reaction mixture was stirred for 1 h at 110 ° C under the pressure necessary to maintain the liquid state of the reaction mixture.

Of the final products obtained, only 5- (p-tolyl) -1H-indole is soluble in water. Upon receipt of this compound, the reaction mixture was processed as described in Example 2.

Reaction mixtures containing other (water-insoluble) indole compounds were treated as follows.

9 ml of water was added to the reaction mixture, and the separated solid phase, which contains the catalyst and the product, was filtered through a porous glass filter. In order to remove the catalyst, the resulting solid phase was dissolved in chloroform, the chloroform insoluble catalyst was filtered off, the filtrate was dried over sodium sulfate and then evaporated in vacuo.

The reagents used, the products obtained and their physical constants, as well as practical yields (%) are shown in Table 5.

Table 5 Product Reagent ¹ H-NMR (300 MHz, CDCl ₃ ) Exit, % 5- (4-Ethoxy-3-methylphenyl) -1H-indole 2- (4-Ethoxy-3-methylphenyl) -1,3,2-dioxaborolan 8.10 (bs, 1H), 7.83 (s, 1H), 7.43 (m, 4H), 7.22 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 4.11 (q, J = 6.9 Hz, 2H), 2.34 (s, 3H), 1.48 (t, J = 6.9 Hz, 3H) 93 5- (4-Methoxy-3-methylphenyl) -1H-indole 2- (4-Methoxy-3-methylphenyl) -1,3,2-dioxaborolan 8.13 (bs, 1H), 7.82 (s, 1H), 7.44 (m, 4H), 7.22 (m, 1H), 6.92 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 3.89 (s , 1H), 2.32 (s, 3H) 90 5- (4-Methoxy-phenyl) -1H-indole 2- (4-Methoxy-phenyl) -1,3,2-dioxaborolan 8.12 (bs, 1H), 7.84 (s, 1H), 7.60 (m, 2H), 7.44 (s, 2H), 7.22 (t, J = 3 Hz, 1H), 7.02 (m, 2H), 6.62 (t , J = 2.4 Hz, 1H), 3.83 (s, 3H) 87 5- (3,4-Dimethoxy-phenyl) -1H-indole 2- (3,4-Dimethoxy-phenyl) -boric acid 82 (bs, 1H), 7.81 (s, 1H), 7.42 (s, 2H), 7.21 (m, 3H), 6.95 (d, J = 8.7 Hz, 1H), 6.59 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H) 94 5- (p-Tolyl) -1H-indole 2- (p-Tolyl) -1,3,2-dioxaborolan 8.13 (bs, 1H), 7.87 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.45 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.24 (m, 1H), 6.6 (m, 1H), 2.43 (s, 3H) 92 5-phenyl-1H-indole Phenylboric acid 8.12 (bs, 1H), 7.90 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.47 (m, 4H), 7.35 (m, 1H), 7.24 (m, 1H), 6.64 (m, 1H) 84 5- (4-Fluoro-phenyl) -1H-indole 2- (4-Fluoro-phenyl) -1,3,2-dioxaborolan 8.13 (bs, 1H), 7.84 (s, 1H), 7.62 (m, 2H), 7.43 (m, 2H), 7.24 (m, 1H), 7.16 (m, 2H), 6.64 (m, 1H) 77

The physical constants of all the products obtained, within the limits of measurement accuracy, were in good agreement with the corresponding parameters of the samples of the authentic product. In the reaction mixtures, the formation of palladium black was not observed; the separated catalyst in all cases retained a lemon yellow color.

Example 6

Obtaining isoquinoline derivatives using the Suzuki coupling reaction using a catalyst according to the invention

General protocol

14 mg (0.25 mol% relative to the substrate 5-bromo-isoquinoline) of the catalyst according to the invention, 3 mmol of dioxaborolan reagent, 553 mg (4 mmol) of potassium carbonate and 416 mg (2 mmol) of 5-bromo-isoquinoline were weighed into a flask. Then the flask was placed in an argon atmosphere and 10 ml of methanol and 1 ml of water were added. Then the flask was closed and the reaction mixture was stirred for 1 h at 110 ° C under the pressure necessary to maintain the liquid state of the reaction mixture. The resulting reaction mixtures were processed as described in Example 2.

The reagents used, the products obtained and their physical constants, as well as practical yields (%) are shown in Table 6.

The physical constants of all the products obtained, within the limits of measurement accuracy, were in good agreement with the corresponding parameters of the samples of the authentic product. The reaction mixtures in all cases retained a lemon yellow color, and no sign of additional decomposition of the catalyst could be detected.

Example 7

Obtaining biphenyl derivatives using the Suzuki coupling reaction using a catalyst according to the invention

General protocol

14 mg (0.25 mol% relative to the substrate p-bromtoluene) of the catalyst according to the invention, 3 mmol of dioxaborolan reagent, 553 mg (4 mmol) of potassium carbonate and 342 mg (2 mmol) of p-bromtoluene were weighed into a flask. Then the flask was placed in an argon atmosphere and 10 ml of methanol and 1 ml of water were added. Then the flask was closed and the reaction mixture was stirred for 1 h at 110 ° C under the pressure necessary to maintain the liquid state of the reaction mixture. The resulting reaction mixtures were processed as described in Example 5.

The reagents used, the products obtained and their physical constants, as well as practical yields (%) are shown in Table 7.

Table 7 Product Reagent ¹ H-NMR (300 MHz, CDCI ₃ ) Exit, % 4-ethoxy-3,4'-di-methylbiphenyl 2- (4-Ethoxy-3-methylphenyl) -1,3,2-dioxa-borolane 7.48 (m, 2H), 7.37 (m, 2H), 7.24 (m, 2H), 6.88 (m, 1H), 4.09 (q, J = 6.9 Hz, 2H), 2.41 (s, 3H), 2.32 (s, 3H), 1.47 (t, J = 6.9 Hz) 95.5 4-methoxy-3,4'-di-methylbiphenyl 2- (4-Methoxy-3-methylphenyl) -1,3,2-dioxa-borolane 7.48 (m, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 3.89 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H) 97

The physical constants of all the products obtained, within the limits of measurement accuracy, were in good agreement with the corresponding parameters of the samples of the authentic product. The reaction mixtures in all cases retained a lemon yellow color, and no sign of additional decomposition of the catalyst could be detected.

Example 8

Obtaining stilbene derivatives using the Heck coupling reaction using a catalyst according to the invention

Derivatives of stilbene were obtained by the reaction of styrene with various aryl bromides, as shown in the following reaction scheme:

General protocol

552 mg (4 mmol, 2 equiv.) K ₂ CO ₃ , 14 mg (0.25 mol%, calculated on the substrate aryl bromide) of the catalyst according to the invention, 312 mg (0.343 ml, 3 mmol, 1.5 equiv.) Styrene , 2 mmol (1 equiv.) Of aryl bromide substrate and 10 ml of a 10: 1 mixture of methanol and water were loaded into a Schlenk vessel dried in an oven. The reaction was carried out at 110 ° C for 3 hours or 20 hours, as shown in Table 8. The degree of chemical conversion was determined by subjecting the reaction mixture to GC (gas chromatography), and then the product was isolated. For tests No. 1, 2, 3, and 5, the products precipitated from the mixture upon cooling, so that they could be isolated by simple filtration; while for tests No. 4, 6 and 7, the products were isolated using flash chromatography.

The results are presented in Table 8.

Table 8 Test No. Aryl bromide Chemical conversion,% Practical yield,% F B AT G D 3 hours 20 hours one H F H H H 95 - 73 2 H H NO ₂ H H one hundred - 67 3 H H Me H H one hundred - 93 four Ome H Ome H H 57 78 60 5 H Me H Me H 98 - 96 6 Me H H H Me 53 64 38 7 iPr H iPr H iPr 90 - 33

NMR data for the resulting stilbene derivatives are as follows:

(E) -3-Fluorostilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.41-7.22 (m, 4H), 7.11 (s, 1H), 7.10 (s, 1H), 6.99-6.94 (m, 1H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 163.5 (C, d, J = 244 Hz), 139.9 (C, d, J = 7.65 Hz), 137.1 (C), 130.3 (CH, d , J = 8.18 Hz), 129.0 (CH), 128.2 (CH), 127.7 (CH, d, J = 2.70 Hz), 126.9 (CH), 122.7 (CH, d, J = 2.78 Hz), 114.62 (CH, d, J = 21.5 Hz), 113.0 (CH, d, J = 21.5 Hz).

(E) -4-Nitrostilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23-8.21 (m, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 7, 5 Hz, 2H), 7.43-7.25 (m, 4H), 7.14 (d, J = 16.5 Hz, 1H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 147.0 (C), 136.4 (C), 133.6 (CH), 129.1 (CH), 127.3 (CH), 127.1 (CH), 126.5 (CH), 124.4 (CH).

(E) -4-Methylstilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.41-7.36 (m, 2H), 7.31-7.26 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (s, 2H), 2.40 (s, 3H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 137.8 (C), 137.8 (C), 134.8 (C), 129.7 (CH), 128.9 (CH), 128.0 (CH), 127.7 (CH) , 126.7 (CH), 21.5 ( CH _3).

(E) -2,4-Dimethoxystilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J = 8.4 Hz, 3H), 7.42 (d, J = 16.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.24 (dd, J = 4.9 Hz, 12.1 Hz, 1H), 7.02 (d, J = 16.5 Hz, 1H), 6.53 (dd, J = 2.2 Hz, 9.9 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 3.88 (s, 1H), 3.84 (s, 1H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 160.5 (C), 138.3 (C), 128.5 (CH), 127.2 (CH), 127.0 (CH), 126.9 (CH), 126.3 (CH), 123.3 (CH), 119.5 (C), 105.0 (CH), 98.5 (CH), 55.5 (CH ₃ ), 55.4 (CH ₃ ).

(E) -3,5-Dimethylstilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55-7.53 (m, 2H), 7.41-7.36 (m, 2H), 7.31-7.26 (m, 1H), 7.18 ( s, 2H), 7.11 (d, J = 2.4 Hz, 2H), 6.95 (s, 1H), 2.38 (s, 6H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 138.3 (C), 137.5 (C), 129.7 (CH), 129.1 (CH), 128.9 (CH), 128.5 (CH), 127.7 (CH), 126.7 (CH), 124.7 (CH), 21.5 (CH ₃ ).

(E) -2,6-Dimethylstilbene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54-7.52 (m, 2H), 7.42-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.13 ( d, J = 16.8 Hz, 1H), 7.1 (m, 3H), (m, 3H), 6.63 (d, J = 16.8 Hz, 1H), 2.39 (s, 6H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 137.6 (C), 137.0 (C), 136.2 (C), 134.0 (CH), 128.7 (CH), 127.9 (CH), 127.6 (CH), 126.9 (CH), 126.7 (CH), 126.3 (CH), 21.0 (CH ₃ ).

(E) -2,4,6-Triisopropylstilbene: ¹ H NMR (300 M Hz, CDCl ₃ ) δ 7.54-7.52 (m, 2H), 7.43-7.38 (m, 2H), 7.33-7.26 (m, 1H) , 7.22 (d, J = 16.5 Hz, 1H), 7.07 (s, 2H), 6.52 (d, 16.8 Hz, 1H), 3.31 (h, 6.9 Hz, 2H), 2.94 (h, J = 6.9 Hz, 1H); 1.33-1.23 (m, 18H); ¹³ C NMR (ATP) (75 M Hz, CDCl ₃ ) δ 142.4 (C), 141.4 (C), 132.3 (C), 128.6 (CH), 127.7 (C), 123.4 (CH), 122.1 (CH), 121.7 (CH), 121.0 (CH ), 115.3 (CH), 29.0 (CH), 24.9 (CH), 18.7 (CH _3), 18.5 (CH _3).

Example 9

Preparation of Phenyl-Ethylene Derivatives Using the Sonogashira Combination Reaction Using the Catalyst of the Invention

Derivatives of phenylacetylene were obtained by the reaction of phenylacetylene with various aryl bromides, as shown in the following reaction scheme:

General Protocol:

276 mg (2 mmol, 1 equiv.) K ₂ CO ₃ , 7 mg (0.25 mol%, calculated on the substrate aryl bromide) of the catalyst according to the invention, 0.165 ml (1.5 mmol, 1.5 equiv.) Of phenylacetylene, 1 mmol (1 equiv.) Of aryl bromide substrate and 5 ml of solvent [solvent (a): 5: 1 mixture of methanol and water; solvent (b): n-butanol; solvent (c): glycerol formal] was loaded into a Schlenk vessel dried in an oven. The reaction was carried out at 110 ° C for 3 hours or 24 hours, as shown in Table 9. The quantities of the products were determined by subjecting the reaction mixture to GC.

The results are presented in Table 9.

Table 9 Test No. Aryl bromide Solvent After 3 hours After 24 hours BUT B AT G Converted,% Product% Converted,% Product% one H Ome Me H (but) 47 43 71 57 2 H NO ₂ H H (but) 88 43 one hundred 56 3 H CH ₃ H H (but) 51 48 81 78 four iPr iPr H iPr (but) 10 8 97 46 5 H Ome Me H (b) 91 65 one hundred 66 6 H NO ₂ H H (b) one hundred 78 - - 7 H Me H H (b) one hundred 84 - - 8 iPr iPr H iPr (at) 36 31 one hundred 87

NMR data for the resulting phenylacetylene derivatives are as follows:

1-Methyl-4- (phenylethinyl) benzene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (d, J = 8.0 Hz, 2H), 7.26-7.22 (m, 5H), 6.70 (d, J = 8.3 Hz, 1H), 3.75 (s, 3H), 2.13 (s, 3H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 158.2 (C), 133.9 (CH), 131.5 (CH), 130.6 (CH), 128.5 (CH), 128.3 (CH), 127.9 (CH), 123.8 (C), 109.9 (CH), 89.9 (C), 55.4 (CH), 16.1 (CH).

1-Nitro-4- (phenylethynyl) benzene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.17 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H) 7.58-7.55 (m, 2H); 7.41-7.38 (m, 3H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 147.0 (C), 132.3 (CH), 131.9 (CH), 130.3 (C), 129.4 (CH), 129.0 (CH), 123.7 (CH), 122.2 (C), 94.8 (C), 87.7 (C).

1-Methyl-4- (phenylethinyl) benzene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.57 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.40-7.35 ( m, 3H), 7.20 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H); ¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 138.6 (C), 131.8 (CH), 131.7 (CH), 129.3 (CH), 128.5 (CH), 128.3 (CH), 123.7 (C), 120.4 (C), 89.8 (C), 89.0 (CH), 21.7 (CH ₃ ).

Phenyl- (2,4,6-triisopropyl-phenyl) -acetylene: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (dd, J = 8.0 Hz, 1.4 Hz, 2H), 7.43-7.35 ( m, 3H), 7.07 (s, 2H), 3.65 (sept, J = 6.9 Hz, 2H), 2.96 (sept, J = 6.9 Hz, 1H), 1.36 (d, J = 6.9 Hz , 12H), 1.32 (d, J = 6.9 Hz, 6H);

¹³ C NMR (ATP) (75 MHz, CDCl ₃ ) δ 150.9 (C), 149.5 (C), 131.5 (CH), 128.6 (CH), 128.1 (CH), 124.6 (CH), 120.7 (CH), 118.7 (C), 97.0 (C), 87.3 (C), 4.9 (CH ₃ ), 32.2 (CH ₃ ), 24.2 (CH ₃ ), 23.6 (CH ₃ ).

The above reaction was repeated using 2-bromo-3-methyl-but-2-ene as a substrate. The results are shown in Table 10.

Table 10 Test No. Solvent After 3 hours After 24 hours Conversion% Product% Conversion% Product% one (but) 22 10 64 40 2 (b) 24 fifteen 84 28 3 (at) 93 87 one hundred 94

NMR data for the resulting product are as follows: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-7.39 (m, 2H), 7.34-7.22 (m, 3H), 2.02 (s, 3H), 1.89 (s , 3H), 1.79 (s, 3H).

Example 10

Obtaining N-phenylpiperidine using the Buchwald reaction using the compound according to the invention as a catalyst

224 mg (2 mmol) of potassium tert-butoxide, 70 mg (0.25 mol%, calculated on the bromobenzene substrate) of the catalyst according to the invention, 105 μl (1 mmol) of bromobenzene, 198 μl (2 mmol) of piperidine and 5 ml of solvent were charged into a Schlenk vessel dried in an oven. The reaction mixture was heated in an oil bath at 110 ° C for 24 hours, then allowed to cool to room temperature and evaporated under reduced pressure. To obtain the desired product, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31-7.26 (m, 2H), 7.00-6.97 (m, 2H), 6.89-6.84 (m, 1H), 3.19 (t, J = 5.6 Hz, 4H ), 1.79-1.72 (m, 4H), 1.64-1.59 (m, 2H).

The results of tests carried out in various solvents are shown in Table 11.

Table11 Test No. Solvent Conversion% after 3 hours after 24 hours one Toluene 40 47 2 DMSO (dimethyl sulfoxide) 35 37

Example 11

In the test reactions, methanol and n-butanol were used as solvents. Styrene recovery was tested using, in all cases, a hydrogen pressure of 6 bar. 21 mg of the catalyst of formula (I) (1 mol% with respect to the styrene substrate), 1 mmol of styrene and 10 ml of solvent were placed in the reactor. First, the flask was washed with gaseous argon, then it was filled with gaseous H2 (6 bar). The reaction mixture was stirred for 6 hours at 110 ° C at a temperature of 110 ° C. Reaction conversion was monitored by gas chromatography

Screening for the Superstable Pd (0) Catalyst for Hydrogenation of Styrene

Claims (18)

1. A method of obtaining a complex of tri- [3,5-bis (trifluoromethyl) phenyl] phosphine and palladium (0), characterized in that the palladium (II) salt is reacted with tri- [3,5-bis (trifluoromethyl) -phenyl] -phosphine and palladium (II) are reduced to palladium (0) in the resulting complex salt. 2. The method according to claim 1, characterized in that the reaction of the palladium (II) salt is carried out with at least a four-fold molar excess of tri- [3,5-bis (trifluoromethyl) phenyl] phosphine. 3. The method according to claim 1, characterized in that the reaction of the palladium (II) salt with tri- [3,5-bis (trifluoromethyl) phenyl] phosphine and the reduction of palladium (II) to palladium (0) is carried out in one reaction vessel without isolation of intermediate compounds. 4. The method according to claim 1, characterized in that palladium dichloride is used as the palladium (II) salt. 5. The method according to claim 1, characterized in that the recovery is carried out with hydrazine hydrate. 6. A catalyst for coupling reactions of C-C and C-heteroatoms and for hydrogenation reactions, which is a complex of tri- [3,5-bis (trifluoromethyl) phenyl] phosphine and palladium (0) obtained by the method according to claim 1. 7. The catalyst according to claim 6, characterized in that its melting point during the DSC test (differential scanning calorimetry) in an inert atmosphere is 220 ° C. 8. The catalyst according to claim 6, characterized in that its decomposition temperature when testing the DSC in air at atmospheric pressure is 169.5 ° C. 9. A catalyst according to claim 6, characterized by the following NMR spectral data: ¹ H-NMR (300 MHz, THF-d ₈ (tetrahydrofuran), δ = 3,58 million ^-1) 8,17 (s, 12 H), 7 84 (s, 24 N); ¹³ C-NMR (75 MHz, THF-d _8, δ = 67,3 million ^-1), 138.1 (C), 133,7 (q, J = 38,7 Hz, C), 133.4 (CH ), 126.3 (CH), 123.4 (q, J = 271.57 Hz, CF ₃ ); ³¹ P-NMR (300 MHz, THF-d ₈ ) 28.77; ¹⁹ F-NMR (300 MHz, THF-d ₈ ) -62.94. 10. The catalyst for the reactions of combining CC and C-heteroatoms and for hydrogenation reactions, which is a complex of tri- [3,5-bis (trifluoromethyl) phenyl] phosphine and palladium (0), characterized by the following NMR spectrum data: ¹ H-NMR (300 MHz, THF-d ₈ (tetrahydrofuran), δ = 3,58 million ^-1) 8,17 (s, 12 H), 7,84 (s, 24 H); ¹³ C-NMR (75 MHz, THF-d _8, δ = 67,3 million ^-1), 138.1 (C), 133,7 (q, J = 38,7 Hz, C), 133.4 (CH ), 126.3 (CH), 123.4 (q, J = 271.57 Hz, CF ₃ ); ³¹ P-NMR (300 MHz, THF-d ₈ ) 28.77; ¹⁹ F-NMR (300 MHz, THF-d ₈ ) -62.94. 11. The catalyst of claim 10, characterized in that its melting point during the DSC test in an inert atmosphere is 220 ° C. 12. The catalyst according to claim 10 or 11, characterized in that its decomposition temperature during the DSC test in air at atmospheric pressure is 169.5 ° C. 13. The use of the catalyst according to any one of claims 6-12 in the reactions of the combination of C-C and C-heteroatom, as well as for hydrogenation. 14. The application of item 13, where the reaction is a cross-reaction CC. 15. The use of claim 14, wherein the cross-coupling reaction is a Suzuki coupling, Heck coupling, or Sonogashira coupling. 16. The application of item 13, where the amount of catalyst used in the reaction per one mol of substrate is 0.25 mol. % or less. 17. The application of item 13, where the reaction is a reaction of a combination of C-N. 18. The application of clause 17, where the reaction is a combination of Buchwald.

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