CN116621774A - Synthesis method of allylic aza-aryl methylamine compound - Google Patents
Synthesis method of allylic aza-aryl methylamine compound Download PDFInfo
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- CN116621774A CN116621774A CN202310538208.8A CN202310538208A CN116621774A CN 116621774 A CN116621774 A CN 116621774A CN 202310538208 A CN202310538208 A CN 202310538208A CN 116621774 A CN116621774 A CN 116621774A
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- methylamine
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- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 125000000746 allylic group Chemical group 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- -1 allyl aza aryl methylamine compounds Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 238000005937 allylation reaction Methods 0.000 claims abstract description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 16
- 229910052723 transition metal Inorganic materials 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 13
- 239000003341 Bronsted base Substances 0.000 claims description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052786 argon Inorganic materials 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000003624 transition metals Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- AWTDFKHVMGEMPB-UHFFFAOYSA-N C1=CC=CC=2OC3=CC=CC=C3NC12.C1(=CC=CC=C1)PC1=CC=CC=C1 Chemical compound C1=CC=CC=2OC3=CC=CC=C3NC12.C1(=CC=CC=C1)PC1=CC=CC=C1 AWTDFKHVMGEMPB-UHFFFAOYSA-N 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000010189 synthetic method Methods 0.000 claims 2
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 238000006880 cross-coupling reaction Methods 0.000 claims 1
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 abstract description 4
- 230000005595 deprotonation Effects 0.000 abstract description 3
- 238000010537 deprotonation reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 241001480043 Arthrodermataceae Species 0.000 abstract description 2
- 230000000843 anti-fungal effect Effects 0.000 abstract description 2
- 230000037304 dermatophytes Effects 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 238000001228 spectrum Methods 0.000 description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 18
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 239000000758 substrate Substances 0.000 description 11
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 230000000171 quenching effect Effects 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 3
- LQPVTFUPUUWMIV-UHFFFAOYSA-N 4-(pyridin-2-ylmethyl)morpholine Chemical compound C=1C=CC=NC=1CN1CCOCC1 LQPVTFUPUUWMIV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- XDBTZKGSODUZAM-UHFFFAOYSA-N 4-(pyridin-2-ylmethyl)thiomorpholine Chemical compound C=1C=CC=NC=1CN1CCSCC1 XDBTZKGSODUZAM-UHFFFAOYSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 150000007527 lewis bases Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Abstract
The invention provides a synthesis method of an allylic aza-aryl methylamine compound. The aza aryl derivative and allyl carbonate react under the catalysis of palladium acetate to prepare a series of allyl aza aryl methylamine compounds. Azaarylmethylamine derivatives are commonly found in biological medicines and natural products, and allylation products with benzyl deprotonation can be used as an active intermediate with medicinal value, and have certain antifungal activity on dermatophytes. Compared with the traditional method, the palladium-catalyzed allylic alkylation reaction has the characteristics of economy and high efficiency, adopts a one-pot method with simple operation to carry out the reaction, does not need harsh reaction conditions such as high temperature, high pressure and the like, and improves the synthesis process to a great extent.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of an allylaza-arylmethylamine compound.
Background
Azaarylmethylamine derivatives are commonly found in biological medicines and natural products, and allylation products with benzyl deprotonation can be used as an active intermediate with medicinal value, and have certain antifungal activity on dermatophytes.
Conventional methods for synthesizing such materials are typically carried out by imine and pre-prepared allylic metal reagents. In 2016, the Walsh group reported that a palladium-catalyzed Cr (CO) 3 activated benzyl nucleophile reacted with a cyclic or chain allyl carbonate synthesized a series of allyl-substituted products with high yields and good chemoselectivity. However, the reaction system needs to be added with an activating group, so that the reaction steps are complicated, and the atom economy of the reaction is reduced. Thus, in situ deprotonation of the substrate is particularly important for allylic alkylation without the use of activating groups. In the process of synthesizing the allylaza-aryl methylamine compound, the substrate can be deprotonated in situ without activating groups, and the allylic alkylation reaction is carried out, so that the compound is efficiently prepared.
Disclosure of Invention
The invention discloses a synthesis method of an allylic aza-aryl methylamine compound, belonging to the field of organic synthesis. The invention uses aza-aryl methylamine shown in formula 1 and allyl carbonate shown in formula 2 to mix with organic solvent to make allylation reaction of aza-aryl methylamine in the presence of transition metal catalyst and Bronsted base, and synthesizes allyl aza-aryl methylamine shown in formula 3 and its derivative. The preparation method is simple, convenient and mild in condition, is suitable for large-scale production, and has important influence on synthesis of the compounds. The specific scheme is as follows:
the synthesis process of allylazaarylmethylamine compound includes mixing allylic azaarylmethylamine compound shown in the formula 1 and allylic carbonate compound shown in the formula 2 with organic solvent in the presence of transition metal catalyst and Bronsted base to synthesize allylic azaarylmethylamine compound shown in the formula 3.
Wherein R is 1 、R 2 Selected from methyl, ethyl, phenyl, benzyl, morpholine ring, N-methylmorpholine ring and thiomorpholine ring, R 3 Selected from hydrogen, phenyl.
Preferably, R 1 、R 2 Selected from morpholine rings and thiomorpholine rings, R 3 Selected from hydrogen, phenyl.
More preferably, R 1 、R 2 Selected from morpholine rings, R 3 Selected from hydrogen.
Preferably, the reaction is carried out under the protection of inert gas, and preferably, the inert gas is nitrogen or argon;
preferably, the synthesis occurs in the presence of a transition metal catalyst, a bronsted base, a phosphine ligand and an organic solvent.
Preferably, the transition metal catalyst is a palladium catalyst; the Bronsted base is sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or lithium bis (trimethylsilyl) amide; the phosphine ligand is 4, 6-bis (diphenylphosphine) phenoxazine.
Preferably, the palladium catalyst is palladium acetate.
More preferably, the bronsted base is lithium bis (trimethylsilyl) amide.
Preferably, the organic solvent is 2-methyltetrahydrofuran.
Preferably, the molar ratio of the aza-arylmethylamine of formula 1, the allyl carbonate of formula 2, the Bronsted base, the catalyst and the phosphine ligand is 1:2 to 5:3 to 5:0.025:0.0375, preferably 1:3:4:0.025:0.0375; the reaction temperature is 0℃to 45℃and preferably 0℃to 25℃and more preferably 0 ℃.
Preferably, by the method of the invention, the aza-arylmethylamine allyl methylation compound with the following structure can be synthesized:
the technical scheme of the invention can at least achieve one of the following beneficial effects:
the raw materials adopted by the synthesis method are cheap and easy to obtain;
the method has the advantages that the required operation steps are simple and convenient, extreme heating or cooling is not needed, and the reaction can be carried out only at normal pressure;
r in the present invention 1 、R 2 And R is R 3 The method has wider applicability and can synthesize various compounds with allylic alkylation structures of aza-aryl methylamine.
Drawings
The attached drawings are hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectrograms of the products of the examples, the serial numbers of the attached drawings correspond to the serial numbers of the examples, the attached drawings are hydrogen spectrum nuclear magnetic resonance spectrograms, the attached drawings are carbon spectrum nuclear magnetic resonance spectrograms, such as the hydrogen spectrum nuclear magnetic resonance spectrograms of the products obtained in the example 1 in the attached drawings, and the attached drawings are the carbon spectrum nuclear magnetic resonance spectrograms of the products obtained in the example 1 in the attached drawings; FIG. 2A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 2, and FIG. 2B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 2; FIG. 3A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 3, and FIG. 3B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 3; FIG. 4A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 4, and FIG. 4B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 4; FIG. 5A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 5, and FIG. 5B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 5; FIG. 6A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 6, and FIG. 6B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 6; FIG. 7A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 7, and FIG. 7B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 7; FIG. 8A is a hydrogen nuclear magnetic resonance spectrum of the product obtained in example 8, and FIG. 8B is a carbon nuclear magnetic resonance spectrum of the product obtained in example 8.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following is a further description of the inventive concept in connection with examples to facilitate understanding by those skilled in the art. The following examples are not intended to limit the invention but to facilitate understanding of the present invention by those skilled in the art. The Lewis bases sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide referred in the specification are purchased from Aldrich company, the palladium catalyst is purchased from alfa and Annaiji company, and the organic solvents used in the reaction are ultra-dry solvents and are purchased from carbofuran company. The various raw materials are all purchased from the market, or other medicines are purchased from Sigma-Aldrich, alfa Aesar, TCI China, bruker-400M or Japanese electronic JEOL through simple synthesis.
Example 1
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, the substrate 4- (2-picolyl) -morpholine (0.1 mmol) and the basic lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (28.5 mg,98 percent yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 1A and FIG. 1B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.59(dd，J＝2.8，2.0Hz，1H)，7.63(td，J＝7.7，1.8Hz，1H)，7.27-7.22(m，1H)，7.18-7.13(m，1H)，5.69-5.55(m，1H)，4.96-4.89(m，2H)，3.70-3.68(m，4H)，3.54(t，J＝6.9Hz，1H)，2.70-2.68(m，2H)，2.61-2.51(m，2H)，2.48-2.38(m，2H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：160.1，149.3，136.1，135.2，123.6，122.3，116.9，71.3，67.3，51.1，36.0ppm.
the raw materials in example 1 were changed, and 10 experimental examples were designed as follows, wherein the experiment in the 1 st group is the experiment in example 1, and the nuclear magnetic resonance spectrum of the corresponding product is shown in fig. 1. The serial numbers of the nuclear magnetic resonance spectrograms of the other 2-10 groups of products correspond to the serial numbers of the corresponding examples.
The structural formulas of the products of the examples 1-10 are shown in the table, in the first 10 examples, the types of the two substrates of aza-arylmethylamine and allyl carbonate are different, other raw materials, the amount, the condition and the like are kept consistent, and the final list shows the yield of the products of the examples.
Example 2
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, substrate N, N-dimethyl-2-methylaminopyridine (0.1 mmol) and alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, and the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (17.25 mg,98 percent yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 2A and FIG. 2B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.59(d，J＝5.0Hz，1H)，7.64(td，J＝7.7，1.8Hz，1H)，7.24(d，J＝7.8Hz，1H)，7.17-7.15(m，1H)，5.68-5.60(m，1H)，5.00-4.90(m，2H)，3.51-3.48(m，2H)，2.73-2.62(m，2H)，2.26(s，6H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：160.5，149.2，136.1，135.5，123.6，122.2，116.9，71.6，42.9，36.7ppm.
example 3
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, substrate N, N-diethyl-2-methylaminopyridine (0.1 mmol) and alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, and the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (17.8 mg,87% yield), the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 3A and FIG. 3B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.56(d，J＝4.8Hz，1H)，7.61(td，J＝7.6，1.8Hz，1H)，7.27(d，J＝8.0Hz，1H)，7.14-7.12(m，1H)，5.75-5.66(m，1H)，5.01-4.85(m，2H)，3.90-3.88(m，1H)，2.74-2.63(m，4H)，2.51-2.45(m，2H)，1.01(t，J＝7.1Hz，6H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：149.0，136.5，135.9，123.7，122.0，116.3，66.0，43.7，35.9，13.1ppm.
example 4
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, the substrate N-methyl-N-phenyl-2-methylaminopyridine (0.1 mmol) and the alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, and the microwave tube was sealed and taken out of the glove box. Then the microwave tube was placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and after the addition was completed, the reaction was repeatedThe reaction was continued for 12h at temperature. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (21.5 mg,90% yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 4A and FIG. 4B, and the spectrogram data are: 1 H NMR(300MHz，CDCl 3 )δ：8.62-8.60(m，1H)，7.59(td，J＝7.7，1.8Hz，1H)，7.27-7.14(m，4H)，6.84(d，J＝8.1Hz，2H)，6.73(t，J＝7.2Hz，1H)，5.94-5.81(m，1H)，5.20-5.00(m，3H)，3.18-3.09(m，1H)，2.85(s，3H)，2.85-2.71(m，1H). 13 C{ 1 H}NMR(75MHz，CDCl 3 )δ：160.7，150.2，148.9，136.3，135.8，129.0，121.9，121.8，116.6，116.5，112.8，63.3，35.4，32.0ppm.
example 5
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, the substrate N-methyl-N-benzyl-2-methylaminopyridine (0.1 mmol) and the alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, and the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (11.7 mg,57 percent yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 5A and FIG. 5B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.56(d，J＝4.8Hz，1H)，7.61(td，J＝7.6，1.8Hz，1H)，7.27(d，J＝8.0Hz，1H)，7.14-7.12(m，1H)，5.75-5.66(m，1H)，5.01-4.85(m，2H)，3.90-3.88(m，1H)，2.74-2.63(m，4H)，2.51-2.45(m，2H)，1.01(t，J＝7.1Hz，6H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：149.0，136.5，135.9，123.7，122.0，116.3，66.0，43.7，35.9，13.1ppm.
example 6
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, substrate 4- (2-picolyl) -thiomorpholine (0.1 mmol) and alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, and the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (21.6 mg,92% yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 6A and FIG. 6B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.59-8.58(m，1H)，7.63(td，J＝7.7，1.8Hz，1H)，7.21-7.19(m，1H)，7.17-7.14(m，1H)，5.75-5.67(m，1H)，5.01-4.91(m，2H)，3.68(dd，J＝8.5，6.0Hz，1H)，2.88-2.72(m，5H)，2.68-2.58(m，5H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：159.5，149.1，136.0，135.9，123.6，122.2，116.6，71.3，52.3，35.2，28.5ppm.
example 7
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry with a stirrerDrying the microwave tube. Stirring and coordinating for about 10min, and sequentially adding substrate 1- [ (2-pyridyl) methyl into the reaction solution]Piperazine (0.1 mmol), alkali lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv), the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0℃and tert-butyl allylcarbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, a microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, ethyl acetate (5 mL) is used for filtering, the filtrate is decompressed and distilled to obtain a crude product, finally, the crude product is separated by column chromatography to obtain a brown oily product (18.8 mg,81 percent yield), the hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in FIG. 7A and FIG. 7B, and the spectrogram data are: 1 H NMR(500MHz，CDCl 3 )δ：8.58-8.57(m，1H)，7.62(td，J＝7.7，1.8Hz，1H)，7.23(d，J＝7.8Hz，1H)，7.16-7.13(m，1H)，5.68-5.59(m，1H)，4.96-4.88(m，2H)，3.59(dd，J＝8.6，5.4Hz，1H)，2.78-2.31(m，10H)，2.26(s，3H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：160.1，149.2，136.1，135.5，123.7，122.2，116.8，70.9，55.4，50.1，46.0，36.2ppm.
example 8
In a glove box filled with nitrogen or argon, transition metal palladium acetate (2.5 mol%,0.025 equiv), ligand Nixantphos (3.75 mol%,0.0375 equiv), organic solvent 2-methyltetrahydrofuran (0.5 mL) were added sequentially to a dry microwave tube fitted with a stirrer. After stirring and coordination for about 10 minutes, the substrate 4- (2-picolyl) -morpholine (0.1 mmol) and the basic lithium bis (trimethylsilyl) amide (0.4 mmol,4 equiv) were added sequentially to the reaction solution, the microwave tube was sealed and taken out of the glove box. The microwave tube was then placed in a cold trap at 0deg.C, tert-butyl cinnamyl carbonate (0.3 mmol,3 equiv) was slowly added dropwise, and the reaction was continued at that temperature for 12h. After the reaction, the microwave tube is opened in the air, 3 drops of water are added for quenching reaction, the obtained crude product is transferred to a short chromatographic column filled with silica gel, the filtration is carried out by using ethyl acetate (5 mL), the filtrate is decompressed and distilled to obtain the crude product, the crude productFinally, the product is separated by column chromatography to obtain a brown oily product (22.7 mg,77% yield), and the hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectrograms of the product are respectively shown in fig. 8A and 8B, and the spectrogram data are as follows: 1 H NMR(500MHz，CDCl 3 )δ：8.61-8.59(m，1H)，7.62(td，J＝7.7，1.8Hz，1H)，7.27-7.20(m，5H)，7.17-7.14(m，2H)，6.29(d，J＝15.8Hz，1H)，6.05-6.00(m，1H)，3.70(t，J＝4.7Hz，4H)，3.62(dd，J＝8.1，5.7Hz，1H)，2.84(dd，J＝13.8，7.0Hz，2H)，2.87-2.82(m，2H)，2.61-2.58(m，2H)，2.50-2.46(m，2H). 13 C{ 1 H}NMR(125MHz，CDCl 3 )δ：160.1，149.4，137.8，136.2，132.0，128.6，127.3，127.1，126.1，123.7，122.4，71.6，67.4，51.2，35.1ppm.
example 9
The temperature in example 1 was changed to 25℃and the other conditions were kept unchanged, finally giving the product (20.9 mg,96% yield).
Example 10
The temperature in example 1 was changed to 45℃and the other conditions were kept unchanged, finally giving the product (9.8 mg,45% yield).
Example 11
The amount of t-butyl allylcarbonate in example 1 was reduced from 3 equivalents to 2 equivalents, with the other conditions remaining unchanged, to finally give the product (19.8 mg,91% yield).
Example 12
The amount of t-butyl allylcarbonate in example 1 was increased from 3 equivalents to 5 equivalents, with the other conditions remaining unchanged, to finally give the product (18.9 mg,87% yield).
Example 13
The bronsted base lithium bis (trimethylsilyl) amide of example 1 was converted to sodium bis (trimethylsilyl) amide and the amount of base was reduced from 3-fold to 2-fold, all other conditions remaining unchanged, to finally give the product (11% yield). The 11% yield herein refers to the nuclear magnetic yield measured using dibromomethane as an internal standard after the reaction is completed.
Claims (10)
1. A method for synthesizing an allylic aza-arylmethylamine compound is characterized by comprising the following steps:
the method comprises the steps of mixing nitrogen heteroaryl methylamine shown in a formula 1 with allyl carbonate shown in a formula 2 in the presence of a transition metal catalyst and Bronsted base, and carrying out reduction cross-coupling reaction to synthesize an allyl alkylation product of the nitrogen heteroaryl methylamine shown in a formula 3 and derivatives thereof; wherein R is 1 、R 2 Selected from methyl, ethyl, phenyl, benzyl, morpholine ring, N-methylmorpholine ring and thiomorpholine ring, R 3 Selected from hydrogen, phenyl.
2. The method of claim 1, wherein R 1 、R 2 Selected from methyl, ethyl, phenyl, benzyl, morpholine ring, N-methylmorpholine ring and thiomorpholine ring, R 3 Selected from hydrogen, phenyl.
3. The method of synthesis according to claim 1, wherein the synthesis occurs in the presence of a transition metal catalyst, a phosphine ligand, a bronsted base and an organic solvent.
4. The method of claim 3, wherein the transition metal catalyst is a palladium catalyst; the Bronsted base is potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and lithium bis (trimethylsilyl) amide.
5. The method of claim 3, wherein the palladium catalyst is palladium acetate.
6. A method of synthesis according to claim 3, wherein the phosphine ligand is 4, 6-bis (diphenylphosphine) phenoxazine.
7. The synthetic method according to claim 1, wherein the reaction is carried out under the protection of an inert gas, preferably nitrogen or argon.
8. The method of claim 1, wherein the organic solvent is 2-methyltetrahydrofuran.
9. The synthetic method according to claim 1, wherein the molar ratio of the aza-arylmethylamine represented by formula 1, the allyl carbonate represented by formula 2, the bronsted base, the catalyst and the phosphine ligand is: 1:2-5:3-5:0.025:0.0375; the reaction temperature is 0-45 ℃.
10. The method of claim 1, wherein the aza-arylmethylamines, allyl carbonates and products are in one of the following tables:
the invention discloses a high-efficiency synthesis method of an allylic aza-aryl methylamine compound, belonging to the field of organic synthesis. The invention uses aza-aryl methylamine shown in formula 1 and allyl carbonate shown in formula 2 to mix with organic solvent to make allylation reaction of aza-aryl methylamine in the presence of transition metal catalyst and Bronsted base, to synthesize aza-aryl methylamine shown in formula 3 and its derivative. The preparation method provided by the invention is simple, convenient and mild in condition, is suitable for large-scale production, and has important significance for synthesizing the allylaza-aryl methylamine compounds.
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