A method for catalytic decarbonylation and hydroamination of aromatic formamide and olefin

Abstract

The present invention belongs to the technical field of organic chemistry, and specifically is a method for catalytic decarbonylation and hydroamination of aromatic formamide and olefin. The present invention is to react aromatic formamide with terminal olefin in an organic solvent in the presence of an inert gas atmosphere and a rare earth catalyst to form a decarbonylation and hydroamination product and carbon monoxide. The known addition reaction of formamide and olefin is to obtain an olefin hydroamination carbonylation product or a hydroamination product. The reaction of the present invention has important complementarity with the traditional reaction mode of olefin and formamide; the limited number of known tertiary amines and olefin hydroamination reactions reported in the early stage require the presence of other reaction reagents (such as silane) or step-by-step reactions, and the reaction conditions are harsh and limited to reactions with activated olefins; the reaction of the present invention has the advantages of mild conditions, good substrate universality, no need for additives, etc., and the obtained product is an anti-Markovnikov addition hydroamination product.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for catalytic decarbonylation and hydroamination of aromatic formamides and olefins. Background Art

[0002] Amines are compounds that are widely present in nature, and the conversion of amines is the most frequently used reaction in drug synthesis (J. Med. Chem. 2016, 59, 4443-4458). Among the various synthetic methods of amine derivatives, the hydroamination reaction of alkenes and alkynes is the most atom-economical method for constructing CN bonds. Although most metals in the periodic table have been found to have the potential to catalyze the addition of alkenes and alkynes to NH bonds, these amines are mainly limited to primary and secondary amines (Chem. Rev. 2015, 115, 2596-2697). For the hydrogenation reaction of CN bonds of tertiary amines with alkenes (alkynes), it is limited to multi-component reactions involving a few other reagents (such as silanes), and the reaction conditions are usually harsh and the atom economy is poor (Eur. J. Org. Chem. 2007, 4600–4604; J. Am. Chem. Soc. 2012, 134, 6571-6574). Therefore, developing new activation strategies for tertiary amines and new reaction modes with alkenes (alkynes) is a challenging research topic with important application value.

[0003] Tertiary formamides represent an important class of amine derivatives with good stability, low price and easy availability. Although the addition reaction of such compounds with alkenes and alkynes has been reported, only hydroamine carbonylation products can be obtained (Chem. Lett. 2012, 41, 298-300; J. Am. Chem. Soc. 2013, 135, 11772-11775). If you want to synthesize hydroamination products from tertiary formamides and alkenes (alkynes), you need to adopt a step-by-step method, first deformylation, and then use the separated and purified deprotected amine to react with alkenes (alkynes) for hydroamination. Summary of the invention

[0004] The object of the present invention is to provide a method for catalytic decarbonylation and hydroamination of aromatic formamide and olefin, which has mild reaction conditions, good substrate universality and simple operation.

[0005] The method for catalytic decarbonylation and hydroamination of aromatic formamide and olefin provided by the present invention comprises the following specific steps:

[0006] Aromatic formamide (I) and styrene (II) are used as raw materials, commercial or easily prepared rare earth metal complexes are used as catalysts, and the reaction is carried out in an organic solvent at 25-120° C. for 3-36 hours; after the reaction is completed, the corresponding amine (III) is obtained through separation and purification; the reaction route is as follows:

[0007]

[0008] In the formula, R 1 , selected from H, alkyl, halogen or phenyl; R 2 is selected from alkyl; R is selected from H, alkyl or halogen; X=CH, N or P.

[0009] In the present invention, the ratio of the amount of the raw material styrene (II) to the amount of the raw material formamide (I) is 2-6 times, preferably 3-4 times.

[0010] In the present invention, the organic solvent is selected from conventional polar organic solvents that do not react with reactants and products, such as DME, DMSO, etc., and is preferably N,N-dimethylformamide.

[0011] In the present invention, the mass of the organic solvent used is 10-30 times that of the raw material formamide (I); preferably 15-20 times.

[0012] Furthermore, the catalyst is selected from rare earth alkyl complexes, rare earth aryl complexes, and rare earth amine complexes; the rare earth metal is selected from La, Sm, Yb, Lu, and Y; preferably, it is an amine, alkyl, and aryl complex of La.

[0013] Furthermore, the molar ratio of the rare earth catalyst to the raw material formamide (I) is 0.02-0.2, preferably 0.05-0.15.

[0014] In the present invention, the reaction temperature is 25-120°C, preferably 60-80°C, and the reaction time is generally 3-36 hours, preferably 12-24 hours.

[0015] In the present invention, the separation and purification adopts a column chromatography separation and purification method. After the reaction is completed, the solvent is evaporated from the reaction solution, and the target product is obtained by wet loading and column chromatography separation, purification and drying. The eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 50:1-20:1, preferably 40:1-20:1.

[0016] The present invention uses rare earth metal complexes as catalysts to achieve the catalytic decarbonylation and hydroamination reaction of aromatic formamides and olefins (alkynes) for the first time. Its beneficial effects are mainly reflected in:

[0017] (1) The decarbonylation hydroamination reaction of aromatic formamide and olefin described in the present invention is the first direct hydroamination reaction of tertiary amine compounds and olefins;

[0018] (2) The known addition reaction of formamide with olefins generally produces olefin hydroamination carbonylation products or hydroamidation products. The reaction of the present invention has important complementarity with the conventional reaction mode of olefins with formamide;

[0019] (3) Tertiary formamide is often used as a solvent for organic reactions due to its high stability. The limited number of known tertiary amines reported previously with olefins (alkynes) require the presence of other reagents (such as silane) or are step-wise reactions with harsh reaction conditions and are limited to reactions with activated olefins.

[0020] (4) The reaction of the present invention has the advantages of mild conditions, good substrate universality, and no need for additives. The obtained product is an anti-Markovnikov addition hydrogen amination product, which provides a practical method for the CN bond recombination of formamide. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described below in conjunction with specific implementation cases. It should be understood that the preparation method of the implementation case of the present invention is only used to illustrate the present invention, rather than to limit the present invention, and the protection scope of the present invention is not limited thereto. Under the premise of the concept of the present invention, simple improvements to the preparation method of the present invention belong to the scope of protection claimed in the present invention.

[0022] Example 1

[0023]

[0024] At room temperature, in a glove box, 0.025mmol of the catalyst La[N(TMS)2]3 was added to a 25mL Schlenk reaction bottle with a tetrafluoroethylene stopcock and a magnetic stirrer, and 3mL of DMF was added as solvent. After sufficient stirring and dissolution, 0.50mmol of the compound of the above formula (I) and 1.50mmol of the compound of the above formula (II) were added. The reaction bottle was taken out of the glove box, placed on a heating module, stirred and heated to 60°C, and stirred and reacted at this temperature for 12 hours. After the reaction was completed, the mixture was poured into ethyl acetate, washed with brine, the water layer was separated, the water layer was extracted with ethyl acetate, the organic layers were combined (i.e., the organic layer after washing and the organic layer obtained by extraction were combined), dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure distillation. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate, the volume ratio of the two was 40:1) to obtain the above formula (III), and the yield was 87%. 1 H NMR (CDCl3, 400MHz, ppm): δ7.31-7.15(m,7H),6.75-6.66(m,3H),3.54(t,J H-H =7.5Hz,2H),2.86(s,3H),2.83(t,J H-H =8.1Hz,2H). 13C NMR (CDCl3, 100MHz, ppm): δ148.92, 139.92, 129.37, 128.90, 128.63, 126.29, 116.28, 112.27, 54.84, 38.55, 33.02.

[0025] Example 2: Example 1 was repeated except that the catalyst was replaced by Sm[N(SiMe3)2]3 from La[N(SiMe3)2]3, while other reaction conditions remained unchanged. The yield was 75%.

[0026] Example 3: Example 1 was repeated except that the catalyst was replaced by Lu[N(SiMe3)2]3 from La[N(SiMe3)2]3, while other reaction conditions remained unchanged. The yield was 70%.

[0027] Example 4: Example 1 was repeated except that the catalyst was replaced by Y[N(SiMe3)2]3 from La[N(SiMe3)2]3, while other reaction conditions remained unchanged. The yield was 72%.

[0028] Example 5: Example 1 was repeated except that the catalyst was replaced by La[N(SiMe3)2]3 with La[CH2SiMe3]3, while other reaction conditions remained unchanged. The yield was 80%.

[0029] Example 6: Example 1 was repeated except that the catalyst was replaced by (C5H5)2LaPh from La[N(SiMe3)2]3, while other reaction conditions remained unchanged. The yield was 79%.

[0030] Example 7: Example 1 was repeated with the exception of adjusting the amount of catalyst to 15 mol % and keeping other reaction conditions unchanged. The yield was 85%.

[0031] Example 8: Example 1 was repeated except that the solvent was replaced by DME from DMF and the reaction temperature was adjusted to 60° C., while other reaction conditions remained unchanged. The yield was 67%.

[0032] Example 9: Example 1 was repeated except that the solvent was replaced by DMSO from DMF and the reaction temperature was adjusted to 60° C., while other reaction conditions remained unchanged. The yield was 55%.

[0033] Example 10: Example 1 was repeated with the exception of adjusting the reaction temperature to 80°C while keeping other reaction conditions unchanged. The yield was 83%.

[0034] Embodiment 11

[0035]

[0036] According to the method described in Example 1, 0.50 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the above formula (III) with a yield of 94%. 1 H NMR(CDCl3,400MHz,ppm):δ7.35(t,J H-H =7.2Hz,2H),7.30–7.17(m,5H),6.67(d,J H-H =9.1Hz,2H),3.59(t,J H-H =7.9Hz,2H),2.89(s,3H),2.87(t,J H-H =7.4Hz,2H). 13 C NMR (CDCl3, 100MHz, ppm): δ147.43, 139.54, 129.02, 128.79, 128.58, 126.31, 121.00, 113.29, 54.83, 38.66, 32.86.

[0037] Example 12

[0038]

[0039] According to the method described in Example 1, 0.50 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the above formula (III) with a yield of 77%. 1 H NMR (CDCl3, 400MHz, ppm): δ7.40-7.36 (m, 4H), 7.30 (d, J H-H =7.2Hz,3H),6.80(d,J H-H =8.8Hz,2H),3.62(t,J H-H =8.3Hz,2H),2.97(s,3H),2.93(t,J H-H =7.4Hz,2H),1.40(s,9H). 13 C NMR (CDCl3, 100MHz, ppm): δ146.76,140.05,138.92,128.87,128.58,126.21,126.11,112.06,55.06,38.54,33.82,33.13,31.67.

[0040] Embodiment 13

[0041]

[0042] According to the method described in Example 1, 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the above formula (III) with a yield of 75%. 1 H NMR (CDCl3, 400MHz, ppm): δ8.17(s,1H),7.97(s,1H),7.36–7.11(m,6H),6.98(d,J H-H =8.3Hz,1H),3.59(t,J H-H =7.5Hz,2H),2.90(s,3H),2.86(t,J H-H =7.6Hz,2H). 13 C NMR (CDCl3, 100MHz, ppm): δ139.07, 136.94, 134.22, 128.75, 128.60, 126.40, 118.57, 54.22, 38.16, 32.81.

[0043] Embodiment 14

[0044]

[0045] According to the method described in Example 1, 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the compound of the above formula (III) with a yield of 72%. 1 H NMR (CDCl3, 400MHz, ppm): δ7.43-7.21(m,7H),6.82(d,J H-H =8.1Hz,2H),6.75(t,J H-H =7.2Hz,1H),3.56(t,J H-H =8.0Hz,2H),3.37(q,J=7.0Hz,2H),2.93(t,J H-H =7.7Hz,2H),1.18(t,J H-H =7.0Hz,3H). 13C NMR (CDCl3, 100MHz, ppm): δ147.34, 139.78, 129.43, 128.83, 128.56, 126.26, 116.11, 112.24, 52.64, 45.45, 33.81, 12.37.

[0046] Embodiment 15

[0047]

[0048] According to the method described in Example 1, 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were reacted in DMF (3 mL) under heating (60° C.) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the compound of the above formula (III) with a yield of 57%. 1 H NMR (CDCl3, 400MHz, ppm): δ7.34–7.24(m,2H),7.14(s,4H),6.83–6.70(m,3H),3.57(t,J H-H =7.9Hz,2H),2.93(s,3H),2.85(t,J H-H =7.7Hz,2H),2.37(s,3H). 13 C NMR (CDCl3, 100MHz, ppm): δ148.78, 136.63, 135.65, 129.24, 129.19, 128.64, 116.14, 112.17, 54.86, 38.47, 32.38, 21.03.

[0049] Example 16

[0050]

[0051] According to the method described in Example 1, 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the compound of the above formula (III) with a yield of 88%. 1 H NMR(CDCl3,400MHz,ppm): δ7.44(d,J H-H =8.2Hz,2H),7.29(t,J H-H =7.5Hz,2H),7.10(d,J H-H =8.1Hz,2H),6.75(d,J H-H =7.2Hz,3H),3.57(t,J H-H=7.5Hz,2H),2.89(s,3H),2.84(t,J H-H =7.5Hz,2H). 13 C NMR (CDCl3, 100MHz, ppm): δ148.66, 138.80, 131.56, 130.57, 129.30, 120.00, 116.35, 112.18, 54.56, 38.62, 32.44.

[0052] Embodiment 17

[0053]

[0054] According to the method described in Example 1, 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated (60°C) in DMF (3 mL) in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the compound of the above formula (III) with a yield of 70%. 1 H NMR(CDCl3,400MHz,ppm): δ8.61(d,J H-H =4.7Hz,1H),7.61(t,J H-H =7.5Hz,1H),7.29(d,J H-H =7.4Hz,2H),7.16(d,J H-H =7.6Hz,2H),6.79(d,J H-H =8.1Hz,2H),6.74(t,J H-H =7.2Hz,1H),3.78(t,J H-H =7.4Hz,3H),3.07(t,J H-H =7.4Hz,3H),2.92(s,3H). 13 C NMR (CDCl3, 100MHz, ppm): δ159.88, 149.44, 148.83, 136.42, 129.23, 123.57, 121.32, 116.21, 112.23, 52.96, 38.33, 35.27.

Claims

1. A method for catalytic decarbonylation and hydroamination of aromatic formamides and olefins, characterized in that: Its synthetic route (I) is: The specific steps are: At room temperature, in a glove box, add 0.025 mmol of a catalyst to a 25 mL Schlenk reaction bottle with a tetrafluoroethylene stopper and a magnetic stirrer, wherein the catalyst is La[N(TMS)2]3 or Sm[N(SiMe3)2]3 or Lu[N(SiMe3)2]3 or Y[N(SiMe3)2]3 or La[CH2SiMe3]3 or (C5H5)2LaPh; then add 3 mL of DMF solvent, stir thoroughly to dissolve, then add 0.50 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II); take the reaction bottle out of the glove box, place it on a heating module, stir and heat to 60°C, and stir at this temperature for 12 hours; after the reaction is completed, pour the mixture into ethyl acetate, wash with brine, separate the water layer, extract the water layer with ethyl acetate, combine the washed organic layer and the extracted organic layer, dry with anhydrous sodium sulfate, distill under reduced pressure to remove the solvent, and purify the crude product by flash column chromatography to obtain the target compound (III); Alternatively, its synthetic route (II) is: According to the specific steps of the synthetic route (I), 0.50 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated to 60° C. in 3 mL of DMF in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the target compound (III); Alternatively, its synthetic route (III) is: According to the specific steps of the synthetic route (I), 0.50 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were reacted in 3 mL of DMF at 60° C. in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the target compound (III); Alternatively, its synthetic route (iv) is: According to the specific steps of the synthetic route (I), 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated to 60° C. in 3 mL of DMF in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the target compound (III); Alternatively, its synthetic route (V) is: According to the specific steps of the synthetic route (I), 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated to 60° C. in 3 mL of DMF in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the target compound (III); Alternatively, its synthetic route (VI) is: According to the specific steps of the synthetic route (I), 0.5 mmol of the compound of the above formula (I) and 1.50 mmol of the compound of the above formula (II) were heated to 60° C. in 3 mL of DMF in the presence of 0.025 mmol of catalyst La[N(TMS)2]3 to obtain the target compound (III).

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