CN109851558B - Azepine condensed ring derivative and preparation method and application thereof - Google Patents
Azepine condensed ring derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to an azepine fused ring derivative and a preparation method and application thereof. The invention provides an azepine condensed ring derivative, which has a structural formula shown in a formula (I); wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements or hydrocarbon groups containing functional groups; r is2Is an alkyl group; r3And R4Selected from hydrogen, alkyl or aryl. The invention provides a azepine condensed ring derivative shown in formula (I), which simultaneously comprises a five-membered ring, a six-membered ring and a seven-membered ring, and the outside of the ring contains an aldehyde functional group or a carbonyl functional group which is easy to convert, so that the subsequent conversion can be conveniently carried out, and the azepine condensed ring derivative has good application prospect in the fields of biology, medicines and natural products.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an azepine condensed ring derivative and a preparation method and application thereof.
Background
Azepine fused ring derivatives are widely applied in human production and life, and azepine is a very important nitrogen-containing heterocyclic skeleton, is not only an important skeleton in organic synthesis, but also exists in a plurality of natural products and compounds with physiological activity, such as common medicaments and natural products containing azepine and derivatives thereof, such as lycopodine (Fawcettimine), Toffonia alkaloid (Akagenine), Galantamine (Galantamine), Cephalotaxine (Cepalotaxine) and indole alkaloid (Steoamide). The azepine fused ring derivative has strong physiological activity and medicinal value, and also can be used as a core skeleton of a marketable medicine for treating mental diseases. However, the variety of them existing in nature cannot satisfy people's needs, and needs to be widened.
Therefore, how to broaden the variety of azepine fused-ring derivatives has been one of the focuses of extensive attention of researchers in the field.
Disclosure of Invention
In view of this, the invention provides an azepine fused ring derivative, and a preparation method and an application thereof, which are used for providing a novel azepine fused ring derivative and widening the variety of the azepine fused ring derivative.
The specific technical scheme of the invention is as follows:
an azepine fused ring derivative has a structural formula shown in a formula (I):
wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements or hydrocarbon groups containing functional groups; r2Is an alkyl group; r3And R4Selected from hydrogen, alkyl or aryl.
The invention provides a azepine condensed ring derivative shown in formula (I), which simultaneously comprises a five-membered ring, a six-membered ring and a seven-membered ring, and the outside of the ring contains an aldehyde functional group or a carbonyl functional group which is easy to convert, so that the derivative can be conveniently subjected to subsequent conversion, and has good application prospects in the fields of biology, medicines and natural products.
Preferably, the functional group in the functional group-containing hydrocarbon group is selected from a halogen element, an ester group, a carbonyl group, an amino group, a nitro group, a cyano group, a sulfone group or an acyl group.
Preferably, Ar is phenyl or naphthyl, more preferably phenyl; the aromatic heterocyclic group is preferably a N, O-and/or S-containing heterocyclic group;
the R is2Is methyl.
In the invention, the alkyl containing functional groups is saturated or unsaturated straight chain alkyl, branched chain alkyl or cyclic alkyl, and the cyclic alkyl comprises condensed ring aryl.
Preferably, the azepine fused-ring derivative is selected from
(3, 6-dimethyl-6H-indeno [1, 7-bc)]Aza-5-carbaldehyde),
(6-methyl-3-phenyl-6H-indeno [1, 7-bc)]Aza-5-carbaldehyde),
(1- (6-methyl-3-phenyl-6H-indeno [1, 7-bc)]Aza-5-yl) -ethanone),
(8-fluoro-6-methyl-3-phenyl-6H indeno [1, 7-bc)]Aza-5-carbaldehyde),
(8-chloro-3, 6-dimethyl-6H-indeno [1, 7-bc)]Aza-5-carbaldehyde),
(8-fluoro-3, 6-dimethyl-6H-indeno [1, 7-bc)]Aza-5-carbaldehyde) or
(3, 6-dimethyl-6H-benzo [5,6]]Indeno [1,7-bc ] s]5-Octrexone).
In the prior art, fused ring derivatives are mainly prepared by condensation reaction of amine and carbonyl compound, such as classical Pictet-Spengler cyclization reaction, Schmidt reaction, olefin cyclization double decomposition reaction and the like. However, the yields of the above processes are generally low and the product diversity is limited; meanwhile, compared with the construction of five-membered rings and six-membered rings, the generation of seven-membered rings is more thermodynamically unfavorable, so that the development of a new method for preparing the azepine fused ring derivative becomes more important.
On the other hand, the Heck reaction, which is a carbon-carbon bond coupling reaction of palladium-catalyzed aryl halide derivatives with terminal olefins, has been developed as a powerful synthesis tool for olefin derivatives with wide application value in synthesis and has won the prize of nobel 2010. In view of the development of transition metal catalyzed carbon-hydrogen bond activation, some hydrocarbon carbon-hydrogen bonds that are not functionalized have been developed to directly use as substrates, and oxidation Heck Reaction (Oxidative Heck Reaction) of hydrocarbon carbon-hydrogen bonds and terminal olefins has been implemented to directly construct olefin derivatives. In recent years, the oxidation Heck reaction of the carbon-hydrogen bond of the aromatic hydrocarbon is realized by activating the carbon-hydrogen bond catalyzed by metallocene catalyst such as pentamethylcyclopentadienyl trivalent rhodium and trivalent iridium, and various nitrogen-containing and oxygen-containing heterocyclic compounds are constructed. The invention adopts selective programmed oxidation Heck reaction to synthesize the multi-functionalized complex nitrogen-containing heterocyclic compound.
The invention also provides a preparation method of the azepine fused ring derivative in the technical scheme, which comprises the following steps:
dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent in an oxygen or air atmosphere, carrying out a first reaction under the action of a trivalent rhodium catalyst, and then adding a compound shown in a formula (IV) to carry out a second reaction to obtain the azepine fused ring derivative;
wherein the content of the first and second substances,
the preparation method provided by the invention uses a simple and easily-obtained hydrocarbon carbon-hydrogen bond substrate, realizes carbon-hydrogen bond activation, oxidation Heck reaction and intramolecular aldehyde-amine condensation reaction through a series reaction started by carbon-hydrogen bond activation by a one-pot method, and finally uses oxidative aromatization as a driving force to leave acyl groups, so that the rapid construction of an azepine fused ring molecular skeleton is realized, the simple preparation of multiple fused ring-azepine molecules can be realized, and a value is provided for the application of the azepine fused ring-azepine molecules in the field of biomedicine.
The preparation method has the advantages that the substrate is simple and easy to obtain, the substrate can be compatible with various functional groups and exocyclic aldehyde groups which are easy to convert, and the substrate is wide in application range; the two-step reaction and one-pot synthesis are carried out, and the operation is simple; the first reaction only occurs at the ortho position of the imidate group of the compound shown in the formula (II), and the regioselectivity is good; in the ortho position of the imido ester group of the compound shown in the formula (II), the reaction activity of a carbon-hydrogen bond is superior to that of a carbon-halogen bond, the chemical selectivity is good, and the development requirement of sustainable chemistry is met.
The preparation method adopts the combination of a new substrate and a coupling synthon, realizes the rapid construction of a complex product by a simple substrate through a series reaction, enriches the diversity of bonds formed by the series reaction and the types of the products, and the reaction in the preparation method has good chemical selectivity and regioselectivity and has atom economy and step economy.
In the preparation method, the compound shown in the formula (III) and the compound shown in the formula (IV) are alpha, beta-unsaturated carbonyl compounds, and under the promotion of a trivalent rhodium catalyst, the compound shown in the formula (II) and the alpha, beta-unsaturated carbonyl compounds are subjected to series reaction, wherein the series reaction comprises carbon-hydrogen bond activation, twice oxidation Heck reaction and intramolecular aldehyde-amine condensation, so that a series of polysubstituted azepine fused ring derivatives can be prepared by a high-efficiency and high-selectivity one-pot method. Specifically, the tandem reaction belongs to the tandem reaction of multiple carbon-hydrogen bond functionalization, namely, firstly, under the action of a trivalent rhodium catalyst and a compound shown as a substrate formula (II), the trivalent rhodium catalyst and the compound shown as a substrate formula (II) carry out oxidation Heck reaction type tandem reaction with the compound shown as a formula (III) to obtain an indene compound; and then the indene compound intermediate and a compound shown in a formula (IV) are subjected to a first-order amine-guided oxidation Heck reaction to obtain the azepine fused ring derivative. Under the condition of one-pot method and under the promotion of a trivalent rhodium catalyst, the compound shown in the formula (II) sequentially reacts with the compound shown in the formula (III) and the compound shown in the formula (IV) to generate oxidation Heck reaction, and the polysubstituted polyazepine fused ring derivative shown in the formula (I) is obtained.
In the present invention, the compound represented by the formula (II) can be obtained in one step by an addition reaction of a commercially available arylnitrile compound with ethanol, the compound represented by the formula (III) is a commercially available reagent, and the compound represented by the formula (IV) is a commercially available reagent.
Preferably, the temperature of the first reaction is 80 ℃ to 120 ℃, and more preferably 100 ℃;
the time of the first reaction is 0.5h to 24h, preferably 1 h.
In the invention, the temperature of the second reaction is 80-120 ℃, and more preferably 100 ℃;
the time of the second reaction is 0.5h to 24h, preferably 12 h.
Preferably, the first reaction and the second reaction are carried out under basic conditions.
In the present invention, the base for adjusting the basic condition is selected from sodium acetate, cesium acetate, potassium acetate, sodium carbonate or potassium phosphate, and more preferably sodium acetate.
Preferably, a ligand and/or an oxidizing agent is further added to the first reaction and the second reaction.
Preferably, the inert solvent is selected from the group consisting of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol or water, preferably one or more of 1, 2-dichloroethane, dimethylsulfoxide, toluene, water, ethanol, tetrahydrofuran and 1, 4-dioxane, more preferably 1, 2-dichloroethane.
In the invention, the ligand is silver hexafluoroantimonate and/or silver bis (trifluoromethanesulfonyl) imide, and preferably silver bis (trifluoromethanesulfonyl) imide. The oxidant is selected from silver acetate, silver carbonate, silver triflate, silver nitrate, copper acetate, cuprous halide, copper halide, ferric trihalide or ferric nitrate, preferably cupric acetate.
In the present invention, the trivalent rhodium catalyst is [ CpRh (CH)3CN)3][SbF6]2And/or [ Cp RhCl2]2。
A ligand such as bis (trifluoromethanesulfonimide) silver is used as a chloride ion capture agent of the trivalent rhodium catalyst, so that ligand exchange is carried out on the trivalent rhodium catalyst, and the trivalent rhodium catalyst with leaner electrons is obtained; and oxygen is used as a final oxidant for the oxidation Heck reaction, and the oxidation Heck reaction is preferably carried out under the air condition of one atmosphere, so that the reaction can be efficiently converted.
The invention provides a preparation method of an azepine fused ring derivative shown in a formula (I), which comprises the step of reacting a compound shown in a formula (II), a compound shown in a formula (III) and a compound shown in a formula (IV) in the presence of an inert solvent under the co-promotion of trivalent rhodium and an oxidant such as divalent copper to obtain the azepine fused ring derivative shown in the formula (I).
In the preparation method, under the condition of a simple one-pot method, three components of the imine ester catalyzed by the trivalent rhodium catalyst and two alpha, beta-unsaturated carbonyl compounds are subjected to a Heck reaction for multiple oxidation in series, so that the high-efficiency synthesis of the polysubstituted azepine fused-ring derivative is realized. Specifically, under the condition of an inert solvent, under the promotion of a trivalent rhodium catalyst and under an alkaline condition, simple and easily obtained imidate and an alpha, beta-unsaturated carbonyl compound are used as reaction substrates, and the multi-substituted azepine fused ring derivative is efficiently, quickly, chemically and regioselectively synthesized in a modular manner. The preparation method has the advantages of few steps, simple and convenient operation, wide application range of the substrate, good atom economy, expansion of bonding mode and product type of oxidation Heck reaction, capability of obtaining a series of products of the azepine fused-ring derivatives by adjusting the structure of three components of the substrate, easiness in subsequent conversion of the products of the azepine fused-ring derivatives, and good application value in the fields of biology, medicines and natural products.
Preferably, the molar ratio of the compound represented by the formula (II), the compound represented by the formula (III) and the compound represented by the formula (IV) is 1: 1: 1-1: 3: 5, more preferably 1: 1.5: 2;
the amount of the trivalent rhodium catalyst is 0.1 mol% to 50 mol%, more preferably 0.5 mol% to 5.0 mol%, and still more preferably 1.0 mol% of the amount of the compound represented by the formula (II).
In the invention, the dosage of the ligand is 2 mol% to 50 mol%, more preferably 5 mol% of the dosage of the compound shown in the formula (II);
the amount of the base used is 1 mol% to 100 mol%, more preferably 15 mol%, based on the amount of the compound represented by the formula (II).
The amount of the oxidizing agent is 0.5 to 300 mol%, more preferably 30 mol%, based on the amount of the compound represented by the formula (II).
The concentration of the compound represented by the formula (II) in the inert solvent is 0.01M to 0.5M, preferably 0.05M.
In the present invention, the preparation method preferably comprises the steps of: 0.002mmol [ Cp Rh (CH) was added to the reactor in sequence under an air atmosphere3CN)3][SbF6]20.01mmol of bis (trifluoromethanesulphonylimide) silver, 0.03mmol of sodium acetate, 1mL of 1, 2-dichloroethane, 0.20mmol of ethyl phenylimidate and 0.30mmol of 3-penten-2-one, and then carrying out a first reaction at 100 ℃ for 1h without separation, after the completion of the ethyl phenylimidate reaction detected by TLC, adding 0.40mmol of monosubstituted alpha, beta-unsaturated ketone such as butenone, and then carrying out a second reaction at 100 ℃ for 12 h. After the second reaction is finished, after the filtration by diatomite, separating a second reaction product by using a column chromatography separation technology, wherein 20 g of 400-mesh column chromatography silica gel is used, and a developing agent or an eluent is a solvent with a volume ratio of 20: 1 to 5: 1 and ethyl acetate to obtain the azepine fused ring derivative.
In conclusion, the invention provides an azepine condensed ring derivative, wherein the structural formula of the azepine condensed ring derivative is shown as a formula (I); wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements or hydrocarbon groups containing functional groups; r2Is an alkyl group; r3And R4Selected from hydrogen, alkyl or aryl. The invention provides a azepine condensed ring derivative shown in formula (I), which simultaneously comprises a five-membered ring, a six-membered ring and a seven-membered ring, and the outside of the ring contains an aldehyde functional group or a carbonyl functional group which is easy to convert, so that the subsequent conversion can be conveniently carried out, and the azepine condensed ring derivative has good application prospect in the fields of biology, medicines and natural products.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a schematic representation of 3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 1 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde1H, spectrogram;
FIG. 2 is a schematic representation of 3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 1 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde13C, spectrum;
FIG. 3 shows 6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 2 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde1H, spectrogram;
FIG. 4 shows 6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 2 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde13C, spectrum;
FIG. 5 shows 1- (6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 3 of the present invention]Nuclear magnetic resonance of aza-5-yl) -ethanones1H, spectrogram;
FIG. 6 is a schematic representation of 1- (6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 3 of the present invention]Nuclear magnetic resonance of aza-5-yl) -ethanones13C, spectrum;
FIG. 7 is a schematic representation of 8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 4 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde1H, spectrogram;
FIG. 8 is a schematic representation of 8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 4 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde13C, spectrum;
FIG. 9 shows 8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc ] provided in example 4 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde19F, spectrogram;
FIG. 10 is a schematic representation of 8-chloro-3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 5 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde1H, spectrogram;
FIG. 11 is a schematic representation of 8-chloro-3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 5 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde13C, spectrum;
FIG. 12 is a schematic representation of 8-fluoro-3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 6 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde1H, spectrogram;
FIG. 13 is a drawing of 8-fluoro-3, 6-dimethyl ester provided in example 6 of the present inventionradical-6H-indeno [1,7-bc]Nuclear magnetic resonance of aza-5-carbaldehyde13C, spectrum;
FIG. 14 is a schematic representation of 8-fluoro-3, 6-dimethyl-6H-indeno [1,7-bc ] provided in example 6 of the present invention]Nuclear magnetic resonance of aza-5-carbaldehyde19F, spectrum;
FIG. 15 is a drawing of a 3, 6-dimethyl-6H-benzo [5,6] ne provided in example 7 of the present invention]Indeno [1,7-bc]NMR of Zone-5-Formaldehyde1H, spectrogram;
FIG. 16 is a drawing showing the 3, 6-dimethyl-6H-benzo [5,6] ring provided in example 7 of the present invention]Indeno [1,7-bc ] s]NMR of Zone-5-Formaldehyde13And C, spectrum.
Detailed Description
The invention provides an azepine fused ring derivative and a preparation method and application thereof, which are used for providing a novel azepine fused ring derivative and widening the variety of the azepine fused ring derivative.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
This example carries out the preparation of 3, 6-dimethyl-6H-indeno [1,7-bc ] aza-5-carbaldehyde (1a), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, ethyl benzimidate compound 2a (30.0mg,0.20mmol), crotonaldehyde 3a (24. mu.L, 0.40mmol), and a trivalent rhodium catalyst [ Cp. Rh (CH) were sequentially added under an atmospheric air atmosphere3CN)3][SbF6]2(0.002mmol), sodium acetate (5.0mg,0.06mmol) and 1, 2-dichloroethane (DCE,1mL) at 100 deg.C for 3h, TLC detecting the reaction of ethyl benzimidate compound 2a,then, crotonone 4a (24 mu L,0.40mmol) is added to carry out a second reaction for 9h, after the reaction is finished, the reaction product is cooled to room temperature, and after the suction filtration through the diatomite, the crude product is obtained by concentration. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is selected from the following components in a volume ratio of 10: 1 with ethyl acetate to obtain the product 3, 6-dimethyl-6H-indeno [1,7-bc]Aza-5-carbaldehyde (1a), 42.4mg, 95% yield, 95% purity.
P-3, 6-dimethyl-6H-indeno [1,7-bc]The aza-5-carbaldehyde (1a) was subjected to nmr examination, as shown in fig. 1 and 2, and the results were:1H NMR(400MHz,CDCl3)：δ9.13(d,J＝1.6Hz,1H),8.31(d,J＝1.6Hz,1H),8.12-8.10(m,1H),7.58-7.56(m,1H),7.51-7.45(m,2H),3.99(q,J＝7.6Hz,1H),2.67(s,3H),1.55(d,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)：δ196.7,163.6,150.9,149.8,142.3,138.6,130.4,130.3,130.3,127.8,124.2,121.8,40.2,26.8,17.4。
the embodiment shows that the invention provides a preparation method for quickly constructing the polysubstituted azepine condensed-ring derivative, the azepine condensed-ring derivative simultaneously comprises a five-membered ring, a six-membered ring and a seven-membered ring, and an aldehyde functional group which is easy to convert is contained outside the rings, so that the further conversion is facilitated.
Example 2
This example carries out the preparation of 6-methyl-3-phenyl-6H-indeno [1,7-bc ] aza-5-carbaldehyde (1b), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, ethyl benzimidate compound 2a (30.0mg,0.20mmol), crotonaldehyde 3a (30. mu.L, 0.50mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] were sequentially added under an atmospheric air atmosphere2]2(0.002mmol), silver bistrifluoromethanesulfonylimide (0.006mmol), copper acetate (4mg,0.02mmol), sodium acetate (1.60mg,0.02mmol) and 1, 2-dichloroethane (DCE,1mL) were subjected to a first reaction at 100 ℃ for 3 hours, and phenylketene 4b (30. mu.L) was added after TLC detection of the ethyl benzimidinate compound 2aL,0.50mmol), carrying out a second reaction for 9h, cooling to room temperature after the reaction is finished, carrying out suction filtration through diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is a mixture of 10: 1 with ethyl acetate to obtain the product 6-methyl-3-phenyl-6H-indeno [1,7-bc]Aza-5-carbaldehyde (1b), 51.8mg, 90% yield, 95% purity.
p-6-methyl-3-phenyl-6H-indeno [1,7-bc]The aza-5-carbaldehyde (1b) was subjected to nmr examination, see fig. 3 and 4, and the results were:1H NMR(400MHz,CDCl3)：δ8.97(s,1H),8.27(d,J＝0.8Hz,1H),8.15-8.13(m,1H),7.86(d,J＝7.6Hz,2H),7.66-7.60(m,2H),7.55-7.48(m,4H),4.05(q,J＝7.6Hz,1H),1.59(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ195.2,163.1,151.1,150.8,142.2,138.7,137.4,132.8,132.4,130.9,130.3,130.0(2C),128.5(2C),127.9,124.3,121.8,40.3,17.5。
example 3
This example carries out the preparation of 1- (6-methyl-3-phenyl-6H-indeno [1,7-bc ] azepin-5-yl) -ethanone (1c), which has the reaction formula:
to a 15mL Schlenk reaction tube, ethyl benzimidate compound 2a (30.0mg,0.20mmol), 3-penten-2-one 3b (30. mu.L, 0.50mmol), and trivalent rhodium catalyst [ Cp. multidot.RhCl ] were sequentially added under an atmospheric pressure air atmosphere2]2(0.004mmol), silver bistrifluoromethanesulfonylimide (0.01mmol), copper acetate (4mg,0.02mmol), sodium acetate (1.6mg,0.02mmol) and 1, 2-dichloroethane (DCE,1mL) are subjected to a first reaction at 100 ℃ for 3 hours, after TLC detection of the ethyl benzimidate compound 2a, phenylketene 4b (30 uL, 0.50mmol) is added for a second reaction for 9 hours, after the reaction is finished, the mixture is cooled to room temperature, and after filtration by diatomaceous earth, the mixture is concentrated to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is a mixture of 10: 1 with ethyl acetate to give the product1-1- (6-methyl-3-phenyl-6H-indeno [1, 7-bc)]Aza-5-yl) -ethanone (1c), 50.8mg, 85% yield, 95% purity.
P-1- (6-methyl-3-phenyl-6H-indeno [1, 7-bc)]Aza-5-yl) -ethanone (1c) was examined by nmr with reference to fig. 5 and 6, with the results:1H NMR(400MHz,CDCl3)：δ8.14(dd,J＝3.2Hz,5.2Hz,1H),7.83(d,J＝7.6Hz,2H),7.73(s,1H),7.62(t,J＝7.6Hz,1H),7.57(dd,J＝3.6Hz,5.2Hz,1H),7.52-7.56(m,4H),3.97(q,J＝7.6Hz,1H),2.60(s,3H),1.52(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ197.8,160.7,156.2,150.5,139.2,138.9,137.7,133.4,131.7,131.5,130.0(2C),129.5,128.7(2C),127.6,124.1,121.4,40.1,23.7,17.6。
this example shows that the chemical transformations of the present invention are compatible with phenyl vinyl ketones, and the resulting fused-ring azepine derivatives contain a 2-phenyl nitrogen-containing heterocyclic skeleton that can be further transformed by nitrogen-assisted hydrocarbon activation.
Example 4
This example carries out the preparation of 8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc ] aza-5-carbaldehyde (1d), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, ethyl p-fluorobenzimidobenzoate 2b (34.0mg,0.20mmol), crotonaldehyde 3a (30. mu.L, 0.50mmol), and a trivalent rhodium catalyst [ Cp. rhoCl ] were sequentially added under an atmospheric pressure air atmosphere2]2(0.006mmol), silver bistrifluoromethanesulfonylimide (0.016mmol), copper acetate (4mg,0.02mmol), sodium acetate (1.6mg,0.02mmol) and 1, 2-dichloroethane (DCE,1mL) at 100 ℃ for 3h of first reaction, after TLC detection of ethyl p-fluorobenzimidate 2b reaction, adding phenylketene 4b (30 uL, 0.50mmol) for 12h of second reaction, cooling to room temperature after reaction, filtering with diatomaceous earth, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is a mixture of 10: 1The product 8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc ] is obtained by the reaction of the petroleum ether and ethyl acetate]Aza-5-carbaldehyde (1d), 52.7mg, 87% yield and 95% purity.
p-8-fluoro-6-methyl-3-phenyl-6H-indeno [1,7-bc]The aza-5-carbaldehyde (1d) was subjected to nmr examination, as shown in fig. 7 to 9, and the results were:1H NMR(400MHz,CDCl3)：δ8.94(s,1H),8.25(s,1H),8.09(dd,J＝5.2Hz,8.0Hz,1H),7.85(d,J＝8.0Hz,2H),7.66-7.62(m,1H),7.53(t,J＝7.6Hz,2H),7.28(d,J＝8.4Hz,1H),7.22-7.18(m,1H),4.03(q,J＝7.6Hz,1H),1.58(dd,J＝0.8Hz,7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ195.2,165.8,163.3,162.1,153.2(d,J＝9.0Hz),151.2,143.7(d,J＝348Hz),137.4,132.9,132.3,130.0(2C),128.5(2C),128.2,123.3(d,J＝9.0Hz),115.5(d,J＝24.0Hz),111.7(d,J＝22.0Hz),40.4,17.4；19F NMR(300MHz,CDCl3)：δ-109.4。
this example shows that the chemical conversion of the present invention can be compatible with fluorine elements widely used in the fields of materials and medicines.
Example 5
This example carries out the preparation of 8-chloro-3, 6-dimethyl-6H-indeno [1,7-bc ] aza-5-carbaldehyde (1e), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, p-chlorobenzeneimidic acid ethyl ester compound 2c (37.0mg,0.20mmol), crotonaldehyde 3a (30. mu.L, 0.50mmol), and trivalent rhodium catalyst [ Cp. multidot.Rh (CH) were sequentially added under an atmospheric air atmosphere3CN)3][SbF6]2(0.002mmol), sodium acetate (5.0mg,0.06mmol) and 1, 2-dichloroethane (DCE,1mL) at 100 ℃ for 3h, detecting by TLC that p-chlorobenzeneformimidate ethyl ester compound 2c has reacted, then adding butenone 4a (30 uL, 0.50mmol) for 9h of second reaction, cooling to room temperature after the reaction is finished, filtering by diatomaceous earth, and concentrating to obtain a crude product. Subjecting the crude product to chromatographic separation using prepared silica gel plates, selecting a developing solventOr the eluent is 10: 1 with ethyl acetate to obtain the product 8-chloro-3, 6-dimethyl-6H-indeno [1,7-bc]Aza-5-carbaldehyde (1e), 44.0mg, 86% yield, 95% purity.
P-8-chloro-3, 6-dimethyl-6H-indeno [1,7-bc]The aza-5-carbaldehyde (1e) was subjected to nmr detection, see fig. 10 and 11, and the results are:1H NMR(400MHz,CDCl3)：δ9.15(d,J＝1.6Hz,1H),8.32(d,J＝1.2Hz,1H),8.03(d,J＝8.4Hz,1H),7.57(s,1H),7.47(dd,J＝1.6Hz,8.4Hz,1H),4.00(q,J＝7.2Hz,1H),2.69(s,3H),1.56(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ196.6,162.5,152.4,150.1,142.1,137.2,136.4,130.6,130.5,128.4,124.8,122.9,40.3,26.9,17.3。
the embodiment shows that the chemical transformation of the invention can rapidly construct multi-substituted azepine fused-ring derivatives, and the rings contain easily-transformed functional groups including chlorine and aldehyde, thereby facilitating the subsequent construction of complex molecules.
Example 6
This example carries out the preparation of 8-fluoro-3, 6-dimethyl-6H-indeno [1,7-bc ] aza-5-carbaldehyde (1f), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, ethyl p-fluorobenzimidobenzoate compound 2b (34.0mg,0.20mmol), crotonaldehyde 3a (30. mu.L, 0.50mmol), and a trivalent rhodium catalyst [ Cp. Rh (CH) were sequentially added under an atmospheric air atmosphere3CN)3Cl2]2(0.002mmol), copper acetate (5mg,0.06mmol) and 1, 2-dichloroethane (DCE,1mL) were subjected to a first reaction at 100 ℃ for 3h, after TLC detection of ethyl p-fluorobenzimidate compound 2b was completed, crotone 4a (30. mu.L, 0.50mmol) was added for a second reaction for 9h, after the reaction was completed, cooled to room temperature, and concentrated to obtain a crude product after diatomaceous earth suction filtration. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is a mixture of 10: 1 petroleum ether and ethyl acetate to obtain the productSubstance 8-fluoro-3, 6-dimethyl-6H-indeno [1,7-bc]Aza-5-carbaldehyde (1f), 39.5mg, 82% yield, 95% purity.
P-8-fluoro-3, 6-dimethyl-6H-indeno [1,7-bc]The aza-5-carbaldehyde (1f) was subjected to nmr examination, as shown in fig. 12 to 14, and the results were:1H NMR(400MHz,CDCl3)：δ9.14(d,J＝1.6Hz,1H),8.31(d,J＝1.2Hz,1H),8.08(dd,J＝5.2Hz,8.4Hz,1H),7.28(d,J＝2.0Hz,1H),7.22-7.17(m,1H),4.00(q,J＝7.2Hz,1H),2.69(s,3H),1.56(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ196.7,165.8,163.3,162.7,153.3(d,J＝9.0Hz),150.0,142.1(dd,J＝2.0Hz,735Hz),130.4,130.1,123.4(d,J＝9.0Hz),115.5(d,J＝23.0Hz),111.6(d,J＝23.0Hz),40.3(d,J＝3.0Hz),26.8,17.4；19F NMR(300MHz,CDCl3)：δ-109.3。
example 7
This example carries out the preparation of 3, 6-dimethyl-6H-benzo [5,6] indeno [1,7-bc ] azepine-5-carbaldehyde (1g), whose reaction scheme is shown below:
to a 15mL Schlenk reaction tube, ethyl 2-naphthylimidinate compound 2d (40.0mg,0.20mmol), crotonaldehyde 3a (30. mu.L, 0.50mmol), and a trivalent rhodium catalyst [ Cp. rho. RhCl ] were sequentially added under an atmospheric pressure air atmosphere2]2(0.006mmol), silver bistrifluoromethanesulfonylimide (0.016mmol), sodium acetate (1.6mg,0.02mmol), copper acetate (4mg,0.02mmol) and 1, 2-dichloroethane (DCE,1mL) are subjected to a first reaction at 100 ℃, after TLC detection of 2-naphthylimidic acid ethyl ester compound 2d is finished, butenone 4a (30 muL, 0.50mmol) is added to perform a second reaction for 9 hours, after the reaction is finished, the mixture is cooled to room temperature, and after the filtration through diatomite, the mixture is concentrated to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein a developing agent or an eluent is a mixture of 10: 1 with ethyl acetate to give the product 3, 6-dimethyl-6H-benzo [5,6]]Indeno [1,7-bc]Zone-5-carboxaldehyde (3g), 42.6mg, 78% yield and 95% purity.
P-3, 6-dimethyl-6H-benzo [5,6]]Indeno [1,7-bc]NMR detection of 5-tolualdehyde (3g) was performed as shown in FIGS. 15 and 16, and the results were:1H NMR(400MHz,CDCl3)：δ9.20(d,J＝1.6Hz,1H),8.61(s,1H),8.36(d,J＝1.2Hz,1H),8.03-8.01(m,1H),7.98(s,1H),7.91(d,J＝7.2Hz,1H),7.57-7.50(m,2H),4.21(q,J＝7.2Hz,1H),2.71(s,3H),1.66(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)：δ196.7,163.2,150.1,146.9,143.0,137.0,134.8,133.2,130.9,130.9,129.2,128.0,127.0,126.0,123.0,121.2,39.9,26.9,18.6。
the embodiment shows that the chemical conversion of the invention can realize the efficient construction of the multiple condensed ring substituted indenoazepine derivative, and provides a foundation for the application of the derivative in the fields of biology and materials.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (4)
1. The preparation method of the azepine fused ring derivative is characterized by comprising the following steps:
dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent in an oxygen or air atmosphere, adding a ligand, an oxidant and a trivalent rhodium catalyst, carrying out a first reaction for 0.5-24 h at 80-120 ℃, adding a compound shown in a formula (IV), and carrying out a second reaction for 0.5-24 h at 80-120 ℃ to obtain an azepine condensed ring derivative shown in a formula (I);
wherein the content of the first and second substances,
ar is phenyl or naphthyl; r1Selected from hydrogen, halogen or halogen-containing elements, ester group, carbonyl group,Alkyl of amino, nitro, cyano, sulfone, acyl; r is2Is methyl; r is3And R4Selected from hydrogen, alkyl or aryl;
the ligand is silver hexafluoroantimonate and/or silver bistrifluoromethanesulfonimide, and the oxidant is selected from silver acetate, silver carbonate, silver trifluoromethanesulfonate, silver nitrate, copper acetate, cuprous halide, copper halide, ferric trihalide or ferric nitrate.
2. The production method according to claim 1, wherein the first reaction and the second reaction are carried out under alkaline conditions.
3. The method according to claim 1, wherein the inert solvent is selected from the group consisting of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol and water.
4. The method according to claim 1, wherein the molar ratio of the compound represented by the formula (II), the compound represented by the formula (III) and the compound represented by the formula (IV) is 1: 1: 1-1: 3: 5;
the dosage of the trivalent rhodium catalyst is 1mol percent to 50mol percent of the dosage of the compound shown in the formula (II).
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