Method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds

Abstract

The present invention belongs to the technical field of the preparation of heterocyclic compounds, and particularly relates to a method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds. An iminium salt reacts with an epoxide to form a hydrogen-bonded adduct, the hydrogen-bonded adduct cleaves to generate free carbene, and the free carbene coordinates with a metal source or a non-metal source to form an N-heterocyclic carbene complex. The coordination conditions of the present invention are simple, without the need for water removal and oxygen removal operations, and can be directly operated in an air atmosphere, coordinated at room temperature, and with a short coordination time. The present invention directly synthesizes an N-heterocyclic carbene complex by using a hydrogen bond formed by an epoxide and an N-heterocyclic ligand to construct an adduct, without solvent treatment, without adding an external basic substance, without a protective gas, and the N-heterocyclic ligand has a wide range of applications.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of heterocyclic compounds, and particularly relates to a method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds. Background Art

[0002] N-heterocyclic carbene complexes are widely used in the fields of medicine, food, energy, etc. Their synthesis methods are mainly divided into the following three categories: 1. dehydrogenation of N-heterocyclic ligands to prepare free N-heterocyclic carbenes and then coordination; 2. cleavage of N-heterocyclic ligand adducts into free carbenes and then coordination; 3. oxidative addition coordination of N-heterocyclic ligands.

[0003] At present, the first method requires relatively harsh and complex reaction conditions; the second method has more synthesis steps for adducts and may also need to go through the harsh reaction process of free carbenes; the third method is applicable to low-valent metal sources that can be oxidized, and has poor generality. Among them, the second type of adducts is divided into organic small molecule adducts (self-adducts, carbon dioxide adducts, aryl adducts, chloroform adducts, etc.) and metal complexes (N-heterocyclic copper complexes, N-heterocyclic silver complexes, N-heterocyclic nickel complexes, etc.), and they exist stably as adducts in the form of covalent bonds and coordination bonds.

[0004] Chinese Patent CN101402644A discloses a method for preparing metal N-heterocyclic carbene complexes. Among them, Method 1: Using acetonitrile as a solvent, adding imidazolium salt and silver oxide in a molar ratio of 1:0.5 - 3, stirring and reacting in the dark at 40 - 60 °C for 2 - 12 hours; then adding active metal powder (manganese, iron, cobalt, nickel or copper) and N-heterocyclic carbene ligand in a molar ratio of 2 - 10:1 and reacting at 40 - 80 °C for 2 - 24 hours. Method 2: Using acetonitrile as a solvent, adding imidazolium salt and active metal powder in a molar ratio of 2 - 10:1, heating in air to 40 - 80 °C and reacting for 12 - 48 hours; filtering the reaction solution, concentrating the filtrate, adding ether to precipitate a solid product, washing the solid with ethanol and ether 2 - 3 times in sequence, then dissolving it with acetonitrile, slowly adding ether, and crystallizing to obtain the metal N-heterocyclic carbene complex. Method 1 of the present invention requires a reaction in the dark, and the reaction conditions are harsh and complex; Method 2 has poor generality of reaction substrates, is only suitable for several metal powders, is not applicable to metal sources and non-metal sources, cannot synthesize N-heterocyclic carbene complexes of zero-valent metals, and requires a long reaction time under heating conditions.

[0005] In summary, the traditional methods for synthesizing N-heterocyclic carbene complexes have problems such as harsh coordination conditions, complex coordination steps, and poor generality. Summary of the Invention

[0006] The object of the present invention is to overcome the technical deficiencies in the existing preparation of N-heterocyclic carbene complexes, and provide a preparation method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds, which coordinates at room temperature and has a short coordination time.

[0007] The method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds. An iminium salt and an epoxide react to form a hydrogen-bond adduct, the hydrogen-bond adduct cleaves to form a free carbene, and the free carbene coordinates with a metal source or a non-metal source to form an N-heterocyclic carbene complex;

[0008]

[0009] Wherein, I is an iminium salt, II is an epoxide, III is a hydrogen-bond adduct, IV is a free carbene, V is an o-haloalkyl alcohol, VI is a metal source or a non-metal source, and VII is an N-heterocyclic carbene complex;

[0010] Y is carbon, oxygen, nitrogen or sulfur; R 1 is hydrogen, an alkyl group or an aryl group; X is chlorine, bromine or iodine; R 2 is hydrogen, an alkyl group, an aryl group, a halogen, a nitro group, an alkoxy group or an ester group; R 3 is hydrogen, an alkyl group, an aryl group, a halogen, a nitro group, an alkoxy group or an ester group; R 4 is hydrogen, an alkyl group, an aryl group, a halogen, a nitro group, an alkoxy group or an ester group; R 5 is hydrogen, an alkyl group, an aryl group, a halogen, a nitro group, an alkoxy group or an ester group.

[0011] Among them:

[0012] The iminium salt is an imidazole salt, a thiazole salt, a pyridine salt, a triazole salt or a pyrazole salt.

[0013] The imidazole salt is 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride, 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride, 1,3-dimethylimidazolium chloride, 1,3-dicyclohexylbenzimidazolium chloride, 1,3-di-tert-butylbenzimidazole chloride, 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium iodide, 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium bromide, 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium chloride or 7,9-bis(2,6-diethylphenyl)-7H-acenaphtho[1,2-d]imidazol-9-ium chloride;

[0014] The thiazole salt is vitamin B1, 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, 3-methylbenzothiazolium iodide or 4,5-dimethyl-3-(2-oxo-2-phenylethyl)thiazolium chloride;

[0015] The pyridine salt is dodecylpyridinium chloride or N-acetylpyridinium chloride.

[0016] The triazolium salts are 2-trimethyl-2,5,6,7-tetrahydropyrrolo[2,1-c][1,2,4]triazolium chloride, 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium chloride, (5aR,10bS)-2-mesityl-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chloride hydrate, (5aR,10bS)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazinium chloride, (-)-(5aS,10bR)-5a,10b-dihydro-2-(2,4,6-trimethylphenyl)-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazolium chloride monohydrate;

[0017] The pyrazolium salt is 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride.

[0018] The metal sources are Au, Pt, Pd, Ru, PdCl2, NiCl2, FeCl2, CrCl3, CoCl2, Al(OTf)3, CuCl, PtCl2, AuCl, Mo(CO)6, Cr(CO)6, Mn(CO)5Br, Ru(PPh3)3Cl2, Cp2ZrCl2, AgNO3, Cp2TiCl2, [PdCl(allyl)]2 or [(p-cymene)RuI2]2; the non-metal sources are B2pin2, S or Se.

[0019] The epoxides are styrene oxide, 1,2-epoxycyclopentane, methyl epoxide, 1,2-epoxybutane, propylene oxide, 1,2-epoxypropane, 1,2-epoxyhexane, epichlorohydrin, 2-(chloromethyl)-2-methyloxirane, cyclohexene oxide, 3,4-epoxytetrahydrofuran, epoxybutane, oxetane, epoxyfluoropropane, A-epoxypinane, glycidyl methyl ether, methyl linoleate oxide, soybean oil oxide, 3-iodooxetane or 2-methyloxirane.

[0020] The dosage ratios of the iminium quaternary salt, the epoxide and the metal source or the non-metal source are (0.1-10):(0.5-10):(0.1-10), wherein, the iminium quaternary salt and the metal source or the non-metal source are in mmol, and the epoxide is in ml.

[0021] During the reaction process, the reaction temperature is room temperature, the stirring time is 1 min - 1 h, and the stirring speed is 200 - 500 revolutions per minute.

[0022] After the reaction is completed, the N-heterocyclic carbene complex is washed with a washing solvent; the washing solvent is petroleum ether, diethyl ether, n-hexane, cyclohexane, dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetonitrile or toluene.

[0023] The dosage ratio of the washing solvent to the iminium quaternary salt is (10 - 200):(0.1 - 10), where the washing solvent is in ml and the iminium quaternary salt is in mmol.

[0024] Compared with other synthesis methods, this reaction process does not require the addition of an alkaline substance and can be directly operated under an air atmosphere.

[0025] The beneficial effects of the present invention are as follows:

[0026] The present invention directly synthesizes the N-heterocyclic carbene complex by using the hydrogen bond formed between the epoxide and the N-heterocyclic ligand to construct an adduct, without solvent treatment, without the addition of an alkaline substance, without a protective gas, and the N-heterocyclic ligand has a wide range of applications.

[0027] The coordination conditions of the present invention are simple, without the need for water and oxygen removal operations, can be directly operated under an air atmosphere, coordinated at room temperature, and have a short coordination time. When the ligand is added to the epoxide, hydrogen bonds can be generated to form a hydrogen bond adduct, and N-heterocyclic carbene coordination can be carried out without the steps of synthesizing the corresponding covalent bond and coordination bond adducts. Moreover, the present invention is suitable for a variety of iminium quaternary salts and strong Lewis acid acceptors that are sensitive to epoxides. The obtained product is directly separated and purified by washing and filtration, without worrying about decomposition through a thin layer chromatography column or a long recrystallization time.

[0028] The present invention has broad application prospects in technical fields such as industrial catalysis, materials science, and biomedicine. Description of the Drawings

[0029] Figure 1 is the 1H NMR spectrum of the N-heterocyclic carbene complex in Example 1;

[0030] Figure 2 is the 13C NMR spectrum of the N-heterocyclic carbene complex in Example 1;

[0031] Figure 3 is the 1H NMR spectrum of the N-heterocyclic carbene complex in Example 2;

[0032] Figure 4 is the 13C NMR spectrum of the N-heterocyclic carbene complex in Example 2;

[0033] Figure 5 is the 1H NMR spectrum of the N-heterocyclic carbene complex in Example 3;

[0034] Figure 6 is the 13C NMR spectrum of the N-heterocyclic carbene complex in Example 3;

[0035] Figure 7 is the 1H NMR spectrum of the N-heterocyclic carbene complex in Example 4;

[0036] Figure 8 is the 13C NMR spectrum of the N-heterocyclic carbene complex in Example 4;

[0037] Figure 9 is the mass spectrum of the reaction solution in Example 4;

[0038] Figure 10 is the single crystal diffraction structure diagram of the N-heterocyclic carbene complex in Example 5. Detailed implementation mode

[0039] The present invention will be further described below in conjunction with embodiments.

[0040] Example 1

[0041] 0.5 mmol of 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride and 2 ml of untreated 1,2-epoxypropane were stirred at room temperature for 0.5 min at a stirring speed of 300 revolutions per minute. Then 0.3 mmol of [PdCl(allyl)]2 was added and stirred at room temperature for 0.5 min at a stirring speed of 300 revolutions per minute. After the reaction was completed, 50 ml of n-hexane was taken to wash the mixture and filtered. The white solid, 1,3-bis(2,4,6-trimethylphenyl)imidazolium carbene allyl palladium chloride complex, was collected with a yield of 70%.

[0042]

[0043] The complex in Example 1 was subjected to NMR detection. The 1H NMR spectrum and 13C NMR spectrum are shown in Figure 1 and Figure 2 .

[0044] The NMR data of 1,3-(2,4,6-trimethylphenyl)imidazolium carbene allyl palladium chloride complex are as follows:

[0045] 1 H NMR(400 MHz, CDCl3): δ 7.08(s, 2H), 6.95(s, 4H), 4.89 - 4.79(m, 1H), 3.84(d, J = 7.2 Hz, 1H), 3.19(d, J = 6.4 Hz, 1H), 2.78(d, J = 6.4 Hz, 1H), 2.31(s, 6H), 2.19(d, J = 10.4 Hz, 12H), 1.79(d, J = 11.6 Hz, 1H), ppm.

[0046] 1313C NMR (100 MHz, CDCl3): δ 183.61, 138.83, 135.88, 135.46, 129.07, 129.01, 122.97, 114.27, 72.35, 49.23, 21.15, 18.31, 18.25, ppm.

[0047] Example 2

[0048] 1 mmol of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium chloride and 3 ml of untreated styrene oxide were stirred at room temperature for 15 min at a stirring speed of 400 revolutions per minute. Then, 0.6 mmol of [PdCl(allyl)]2 was added, and the mixture was stirred at room temperature for 15 min at a stirring speed of 400 revolutions per minute. After the reaction was completed, 80 ml of ethyl acetate was taken to wash the mixture and filtered. The white solid, namely 1,3-bis(2,4,6-trimethylphenyl)imidazolium carbene allyl palladium chloride complex, was collected with a yield of 79%.

[0049]

[0050] The complex of Example 2 was subjected to NMR detection. The 1H NMR spectrum and 13C NMR spectrum are shown in Figure 3 and Figure 4 .

[0051] The NMR data of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ylidene allyl palladium chloride complex are as follows:

[0052] 1 1H NMR (400 MHz, CD3OD): δ 8.94 (d, J = 5.2 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.43 - 8.39 (m, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.70 - 7.61 (m, 3H), 5.97 - 5.87 (m, 1H), 4.71 (d, J = 7.6 Hz, 1H), 4.51 (t, J = 7.6 Hz, 2H), 4.28 (s, 1H), 3.92 (d, J = 14.0 Hz, 1H), 3.17 (s, 1H), 2.06 - 1.97 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H), ppm.

[0053] 1313C NMR (100 MHz, CD3OD): δ 187.87, 154.61, 152.60, 143.00, 134.41, 130.27, 126.29, 125.76, 123.79, 121.33, 113.51, 113.24, 113.05, 74.51, 51.16, 49.92, 23.30, 10.30, ppm.

[0054] Example 3

[0055] 0.5 mmol of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium iodide and 2 ml of untreated 2-methyloxirane were stirred at room temperature for 5 min at a stirring speed of 500 revolutions per minute. Then 0.3 mmol of [(p-cymene)RuI2]2 was added, and the mixture was stirred at room temperature for 5 min at a stirring speed of 500 revolutions per minute. After the reaction was completed, 40 ml of tetrahydrofuran was taken to wash the mixture and filtered. The red solid, i.e., 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazolium carbene p-cymene ruthenium iodide complex, was collected with a yield of 85%.

[0056]

[0057] The complex of Example 3 was subjected to NMR detection. The 1H NMR spectrum and 13C NMR spectrum are shown in Figure 5 and Figure 6 .

[0058] The NMR data of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazolium carbene p-cymene ruthenium iodide complex are as follows:

[0059] 1 1H NMR (400 MHz, CDCl3): δ 9.67 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.17 - 8.15 (m, 1H), 8.08 (t, J = 7.6 Hz, 1H), 7.56 - 7.54 (m, 1H), 7.42 - 7.38 (m, 3H), 6.52 (d, J = 6.0 Hz, 1H), 6.27 (d, J = 4.8 Hz, 1H), 6.11 (d, J = 6.0 Hz, 1H), 5.70 (d, J = 6.0 Hz, 1H), 4.58 - 4.49 (m, 2H), 2.58 - 2.51 (m, 1H), 2.45 (s, 3H), 2.24 - 2.13 (m, 1H), 2.02 - 1.93 (m, 1H), 1.10 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H), ppm.

[0060] 13 13C NMR (100 MHz, CDCl3): δ 196.20, 158.81, 151.70, 141.44, 135.40, 130.34, 125.55, 125.48, 123.14, 113.22, 112.84, 111.90, 109.56, 107.01, 93.39, 92.68, 87.59, 85.40, 51.84, 31.62, 22.82, 22.22, 21.39, 14.08, 11.77, ppm.

[0061] Example 4

[0062] 0.5 mmol of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium chloride and 2 ml of untreated epichlorohydrin were stirred at room temperature for 7.5 min at a stirring speed of 200 revolutions per minute. Then 0.6 mmol of Mo(CO)6 was added and stirred at room temperature for 7.5 min at a stirring speed of 200 revolutions per minute. After the reaction was completed, 60 ml of petroleum ether was taken to wash the mixture and filtered. The yellow solid, namely 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazolium carbene tetracarbonylmolybdenum complex, was collected with a yield of 63%.

[0063]

[0064] The complex of Example 4 was subjected to NMR detection. The 1H NMR spectrum and 13C NMR spectrum are shown in Figure 7 and Figure 8 .

[0065] The NMR data of 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazolium carbene tetracarbonylmolybdenum complex are as follows:

[0066] 1 1H NMR (400 MHz, DMSO-d6): δ 8.86 (dd, J = 5.6 Hz, J = 1.2 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.26 - 8.22 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.57 - 7.49 (m, 3H), 4.57 (t, J = 7.6 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H), ppm.

[0067] 1313C NMR (100 MHz, DMSO-d6): δ 214.33, 207.20, 153.53, 153.36, 141.34, 135.91, 131.68, 125.07, 124.59, 122.45, 114.21, 113.41, 112.08, 50.55, 23.19, 11.51, ppm.

[0068] After the reaction was completed, without washing first, the reaction solution of Example 4 was subjected to high-resolution mass spectrometry analysis, as shown in Figure 9 , the ion source was ESI + , the theoretical molecular weight of the hydrogenation of 1,3-dichloro-2-propanol was 128.9874, and the actual value was 128.9873, with the error within the effective range. This method proved that 1,3-dichloro-2-propanol was generated in the reaction system, indicating that the halogen ion on the imidazolium salt attacked the epoxide to form a hydrogen bond adduct, and this adduct generated an N-heterocyclic carbene after leaving 1,3-dichloro-2-propanol. Only then could the N-heterocyclic carbene coordinate with Mo(CO)6 to synthesize 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazolium carbene tetracarbonyl molybdenum complex.

[0069] Example 5

[0070] 0.5 mmol of 3-methylbenzothiazolium iodide and 2 ml of untreated epichlorohydrin were stirred at room temperature for 2.5 min at a stirring speed of 300 revolutions per minute. Then, 0.3 mmol of [(p-cymene)RuI2]2 was added, and the mixture was stirred at room temperature for 2.5 min at a stirring speed of 200 revolutions per minute. After the reaction was completed, 60 ml of ethyl acetate was taken to wash the mixture and filtered. The red solid, namely 3-methylbenzothiazolium carbene cymene ruthenium iodide complex, was collected with a yield of 77%.

[0071]

[0072] The complex of Example 5 was detected by single crystal diffraction. The single crystal diffraction structure diagram is shown in Figure 10 .

Claims

1. A method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds, characterized in that: The iminium quaternary salt reacts with the epoxide to form a hydrogen bond adduct, the hydrogen bond adduct cleaves to generate free carbene, and the free carbene coordinates with the metal source to form a N-heterocyclic carbene complex; The iminium quaternary salt is 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride, 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium iodide, 3-propyl-1-(pyridin-2-yl)-1H-benzo[d]imidazol-3-ium chloride or 3-methylbenzothiazolium iodide; The metal source is Mo(CO)6, [PdCl(allyl)]2 or [(p-cymene)RuI2]2; The epoxide is styrene oxide, 1,2-epoxypropane, epichlorohydrin or 2-methyloxirane.

2. The method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds according to claim 1, characterized in that: The dosage ratio of the iminium quaternary salt, the epoxide and the metal source is (0.1 - 10):(0.5 - 10):(0.1 - 10), where the iminium quaternary salt and the metal source are in mmol, and the epoxide is in ml.

3. The method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds according to claim 1, characterized in that: During the reaction, the reaction temperature is room temperature, the stirring time is 1 min - 1 h, and the stirring speed is 200 - 500 revolutions per minute.

4. The method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds according to claim 1, wherein: After the reaction is completed, the N-heterocyclic carbene complex is washed with a washing solvent; the washing solvent is petroleum ether, diethyl ether, n-hexane, cyclohexane, dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol, acetonitrile or toluene.

5. The method for synthesizing N-heterocyclic carbene complexes by using hydrogen bonds according to claim 4, characterized in that: The dosage ratio of the washing solvent to the iminium quaternary salt is (10 - 200):(0.1 - 10), where the washing solvent is in ml and the iminium quaternary salt is in mmol.

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