阅读说明：本技术 一种多取代氢化苯并环醚衍生物及其制备方法 (Polysubstituted hydrogenated benzocycloether derivative and preparation method thereof ) 是由 金毅 袁旭 林军 于 2021-07-21 设计创作，主要内容包括：本发明公开了一种多取代氢化苯并环醚衍生物及其制备方法,属于有机化学技术领域,包括I类多取代氢化苯并环醚衍生物或II类多取代氢化苯并环醚衍生物；所述I类多取代氢化苯并环醚衍生物结构通式：所述II类多取代氢化苯并环醚衍生物结构通式：其中R-(1)为甲基或氢；其中R-(2)为甲基、甲氧基、氟、氯、溴、硝基、氰基、乙炔基或三氟甲基；其中n为0或1；其中X为CH-(2)或O。(The invention discloses a polysubstituted hydrogenated benzo cyclic ether derivative and a preparation method thereof, belonging to the technical field of organic chemistry and comprising a I type polysubstituted hydrogenated benzo cyclic ether derivative or a II type polysubstituted hydrogenated benzo cyclic ether derivative; the I type is polysubstituted hydrogenThe structural general formula of the benzo cyclic ether derivative is as follows: the structural general formula of the II type polysubstituted hydrogenated benzocycloether derivative is as follows: wherein R is 1 Is methyl or hydrogen; wherein R is 2 Is methyl, methoxy, fluorine, chlorine, bromine, nitro, cyano, ethynyl or trifluoromethyl; wherein n is 0 or 1; wherein X is CH 2 Or O.)

1. A polysubstituted hydrogenated benzo cyclic ether derivative is characterized by comprising a I type polysubstituted hydrogenated benzo cyclic ether derivative or a II type polysubstituted hydrogenated benzo cyclic ether derivative;

the structural general formula of the I type polysubstituted hydrogenated benzocycloether derivative is as follows:

the structural general formula of the II type polysubstituted hydrogenated benzocycloether derivative is as follows:

wherein R is₁Is methyl or hydrogen;

wherein R is₂Is methyl, methoxy, fluorine, chlorine, bromine, nitro, cyano, ethynyl or trifluoromethyl;

wherein n is 0 or 1;

wherein X is CH₂Or O.

2. The polysubstituted hydrogenated benzo cyclic ether derivative according to claim 1, wherein said class I polysubstituted hydrogenated benzo cyclic ether derivative is synthesized by the following synthetic route:

3. the polysubstituted hydrogenated benzo cyclic ether derivative according to claim 1, wherein said class II polysubstituted hydrogenated benzo cyclic ether derivative is synthesized by the following route:

4. the polysubstituted hydrogenated benzocycloether derivative according to claim 1, characterized by being selected from any one of the following compounds:

5. a preparation method of polysubstituted hydrogenated benzocycloether derivative is characterized by comprising the following steps:

s1, putting aldehyde and a reaction reagent into a reaction tube;

s2, adding solvent cyclic ether, and then adding N, N-dimethylformamide, alkali and a photosensitizer;

s3, stirring for 8 hours at 10-60 ℃ in a light irradiation gas atmosphere, and continuing irradiation until the raw material aldehyde is completely consumed;

and S4, after the reaction is finished, removing the cyclic ether in the reaction solution through reduced pressure distillation, extracting, obtaining a crude product through reduced pressure distillation, and purifying through column chromatography to obtain the final product I type polysubstituted hydrogenated benzo cyclic ether derivative or II type polysubstituted hydrogenated benzo cyclic ether derivative.

6. The process for producing a polysubstituted hydrogenated benzocycloether derivative according to claim 5, wherein the reaction reagent is a solution of ethyl cyanoacetate or a solution of malononitrile.

7. The method for preparing a polysubstituted hydrogenated benzocycloether derivative according to claim 5, wherein the photosensitizer in step S2 is meso-TPP.

8. The process for producing a polysubstituted hydrogenated benzocycloether derivative according to claim 5, wherein the gas atmosphere in step S3 is oxygen or air.

9. The method for preparing a polysubstituted hydrogenated benzocycloether derivative according to claim 5, wherein the irradiation in step S3 is blue light or violet light.

10. Use of a polysubstituted hydrogenated benzocycloether derivative according to any one of claims 1-9, for the preparation of an anticancer, anticoagulant or antibacterial anti-inflammatory drug.

Technical Field

The invention belongs to the technical field of organic chemistry, and particularly relates to a polysubstituted hydrogenated benzocycloether derivative and a preparation method thereof.

Background

The basic skeleton of the hydrogenated benzocycloether is an important medicine structural unit, widely exists in bioactive molecules, and has various treatment application values of resisting cancer, resisting blood coagulation, resisting bacteria and diminishing inflammation and the like. Hydrogenated benzocycloether backbones are also common among natural products and active molecules.

Such as the common narcotic morphine (A), psychostimulant 3, 4-methylenedioxybenzisopropylamine (B), the alkaloid silymarin (C), pterocarpin, and the like.

However, selective and direct C (sp3) -H functionalization provides a direct synthetic method for hydrogenated benzocycloether, multiple analogs can be accessed from a common structural precursor through a core-of-structure multiplexing strategy, and few, but interesting reports have been made on the functionalization of the ether-H bond in one step. Few reports have been made on dehydro-bifunctional saturated cyclic ethers involving sequential metal-catalyzed dehydro [4+2] cycloaddition processes. Tendon dioxy-dehydrogenation and Povarov reactions of N-alkylaniline derivatives with cyclic ethers in the presence of iron or copper catalysts have been reported to obtain the corresponding bifunctional cyclic adducts. Undoubtedly, these dual-functionalized transformations can be used to synthesize structurally complex and diverse organic molecules, but they still face the challenges of the utilization of transition metal catalysts and high reaction temperatures. Therefore, there is an urgent need to develop a more mild and efficient ether α, β -bis C (sp3) -H bond functionalization strategy. The oxidation-bromination reaction of tetrahydrofuran using hydrobromic acid that undergoes an oxidative ring opening/closing tendency has recently been reported, and double functionalization of ethers by oxidative ring cleavage tandem to build multi-ring systems has not previously been reported. In particular, the direct construction of benzofuran, pyran, dioxin derivatives by direct α, β -bis C (sp3) -H bond functionalization of cyclic ethers is a huge challenge.

Domino reaction is designed to directly and efficiently construct hydrogenated benzofuran, hydrogenated benzopyran and hydrogenated benzodioxin derivatives from saturated cyclic ethers. The method for synthesizing the hydrogenated benzo cyclic ether derivative by using the method has the advantages of easily obtained raw materials, cheap catalyst, mild reaction conditions and small environmental pollution, and has very important significance, however, the alpha, beta-carbon of the saturated cyclic ether exists in a manner of a carbon-carbon single bond³The hybrid mode has the lowest energy, the compound is very stable, the prior literature reports that the single C-H activation is realized by almost using metal catalysis or high-temperature reaction, and no report is provided for simultaneously activating two inert C-H groups.

Disclosure of Invention

The invention aims to provide a polysubstituted hydrogenated benzo cyclic ether derivative and a preparation method thereof, and solves the technical problem that no effective synthesis method exists in the hydrogenated benzo cyclic ether derivative in the prior art.

The invention discloses a polysubstituted hydrogenated benzo cyclic ether derivative, which comprises a I type polysubstituted hydrogenated benzo cyclic ether derivative or a II type polysubstituted hydrogenated benzo cyclic ether derivative;

the structural general formula of the I type polysubstituted hydrogenated benzocycloether derivative is as follows:

the structural general formula of the II type polysubstituted hydrogenated benzocycloether derivative is as follows:

wherein R is₁Is methyl or hydrogen;

wherein R is₂Is methyl, methoxy, fluorine, chlorine, bromine, nitro, cyano, ethynyl or trifluoromethyl;

wherein n is 0 or 1;

wherein X is CH₂Or O.

Further, the synthetic route of the I-type polysubstituted hydrogenated benzo cyclic ether derivative is as follows:

further, the synthetic route of the II type polysubstituted hydrogenated benzo cyclic ether derivative is as follows:

further, any one of the following compounds is selected from:

a method for preparing polysubstituted hydrogenated benzocycloether derivative comprises the following steps:

s1, putting aldehyde and a reaction reagent into a reaction tube;

s2, adding solvent cyclic ether, and then adding N, N-dimethylformamide, alkali and a photosensitizer;

s3, stirring for 8 hours at the temperature of 10-60 ℃ in a light irradiation gas atmosphere, and continuing irradiation until the raw material aldehyde is completely consumed;

s4, after the reaction is finished, removing cyclic ether in the reaction liquid through reduced pressure distillation, extracting, obtaining a crude product through reduced pressure distillation, and then purifying through column chromatography to obtain a final product I type polysubstituted hydrogenated benzo cyclic ether derivative or II type polysubstituted hydrogenated benzo cyclic ether derivative;

the reaction reagent is ethyl cyanoacetate solution or malononitrile solution.

Further, the amount of the aldehyde used in the step S1 is 1-20 mmol.

Further, the amount of the reaction reagent used in the step S1 is 3-60 mmol.

Further, the amount of cyclic ether used in said step S2 is 0.15 to 3.0 mol.

Further, in the step S2, the photosensitizer is meso-TPP.

Further, the extraction in the step S2 is performed using saturated water of sodium chloride and ethyl acetate.

Further, the gas atmosphere in the step S3 is oxygen.

Further, the gas atmosphere in the step S3 is air.

Further, in the step S3, blue light is used for illumination.

Further, in the step S3, the illumination is purple light.

Further, the reaction temperature is 40-50 ℃.

Further, the reaction temperature was 50 ℃.

A polysubstituted hydrogenated benzo cyclic ether derivative is used to prepare the medicines for treating cancers, anticoagulation, bacteria and inflammation.

The invention has the beneficial effects that:

1. the polysubstituted hydrogenated benzo cyclic ether compound is synthesized by one-step reaction of a simple and easily available industrial raw material compound under mild conditions, a cheap and environment-friendly synthesis method is provided, and the highly functionalized hydrogenated benzo cyclic ether compound is synthesized more simply, conveniently, efficiently and universally; activation of the α, β -C-H bond of a saturated cyclic ether is very difficult. In the past, conditions such as utilization of transition metal catalysis, high-temperature reaction and the like are generally used, so that the industrial production is not facilitated, and raw materials are expensive and dangerous. The method is characterized in that a metal-free peroxycyclic ether is firstly generated in an oxygen atmosphere under the illumination condition, and then an inert C-H bond can be simultaneously activated through ring opening and closing reaction to construct a complex organic molecule containing a saturated cyclic ether skeleton.

2. In the preparation process, in order to optimize and improve the reaction yield, the reaction solvent type and the irradiation wavelength of the light reaction are screened, and the optimal reaction condition combination is found out, so that the reaction yield is improved to more than 90%.

Detailed Description

In addition, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.

Example 1

Embodiments of the present invention provide a method for preparing a polysubstituted hydrogenated benzocycloether derivative, preparing compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round bottom flask, 20mL of tetrahydrofuran and 4mL of N, N-dimethylformamide are added, meso-TPP is added, 5 mmol% and 0.15mmol of triethylamine are added, a reaction bottle is filled with oxygen, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the purification is carried out by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1 with the yield of 90%. White solid: mp.232.6-233.9 deg.C; 90 percent of yield; IR (KBr, v)_max,cm^-1):3350,3213,2934,2889,2222,1666,1635,1456,1392,1072,1028,961,913.；¹H NMR(600MHz,DMSO-d₆)δ:7.57(dd,J＝6.0,1.6Hz,2H,ArH),7.50–7.42(m,5H,ArH,NH₂),4.37(d,J＝5.1Hz,1H,OCH),3.86(td,J＝8.2,6.3Hz,1H,OCH_αH_β),3.64–3.58(m,2H,ArCH and OCH_αH _β ),3.00(dddd,J＝13.1,7.6,5.0,1.9Hz,1H,CH),2.04(dtd,J＝13.0,8.5,6.4Hz,1H,CH_αH_β),1.27(dtd,J＝13.0,8.5,6.4Hz,1H,CH_αH_β).¹³C NMR(151MHz,DMSO-d₆)δ:148.60,135.07,129.60,129.25,129.18,118.64,112.58,112.49,75.18,74.83,65.94,47.00,43.27,37.58,30.20.HRMS(TOF-ESI⁺):m/z calcd for C₁₇H₁₅N₄O[M+H]⁺,291.1240；found,.291.1242。

Example 2

This embodiment provides, as a preferred embodiment of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, which comprises preparing a compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round bottom flask, 20mL of tetrahydrofuran and 10mL of N, N-dimethylformamide are added, meso-TPP is added, 5 mmol% and 0.15mmol of triethylamine are added, a reaction bottle is filled with oxygen, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the crude product is purified by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1 with the yield of 83%.

Example 3

This embodiment provides, as a preferred embodiment of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, which comprises preparing a compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round bottom flask, 20mL of tetrahydrofuran and 2mL of N, N-dimethylformamide are added, meso-TPP is added, 5 mmol% and 0.15mmol of triethylamine are added, a reaction bottle is filled with oxygen, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the purification is carried out by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1, wherein the yield is 84%.

Example 4

This embodiment provides, as a preferred embodiment of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, which comprises preparing a compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round-bottom flask, 20mL of tetrahydrofuran is added, meso-TPP is added, 10mmol percent of triethylamine is added, 0.15mmol of triethylamine is added, oxygen is filled into a reaction bottle, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the crude product is purified by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1 with the yield of 75 percent.

Example 5

This embodiment provides, as a preferred embodiment of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, which comprises preparing a compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round-bottom flask, 20mL of tetrahydrofuran is added, meso-TPP is added, 5mmol percent of triethylamine is added, 0.15mmol of triethylamine is added, oxygen is filled into a reaction bottle, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the crude product is purified by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1 with the yield of 78 percent.

Comparative example 1

This embodiment provides, as a comparative example of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, which comprises preparing a compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

adding 1.0mmol of benzaldehyde and 3.0mmol of malononitrile into a 50mL round-bottom flask respectively, adding 20mL of tetrahydrofuran, adding meso-TPP, 1mmol of triethylamine, adding 0.15mmol of triethylamine, filling oxygen into a reaction bottle, irradiating for 8h by blue light at 50 ℃, monitoring the reaction by TLC, extracting for 3 times by using saturated sodium chloride aqueous solution and ethyl acetate after the reaction is completed, drying by using anhydrous sodium sulfate, obtaining a crude product by reduced pressure distillation, and then purifying by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1, wherein the yield is less than 50%.

Comparative example 2

This embodiment provides, as a comparative example of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round-bottom flask, 20mL of tetrahydrofuran is added, meso-TPP is added, 1mmol percent and 0.15mmol of triethylamine are added, nitrogen is filled into a reaction bottle, blue light irradiation is carried out for 8 hours at 50 ℃, TLC monitors the reaction, and the reaction does not occur.

Comparative example 3

This embodiment provides, as a comparative example of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

adding 1.0mmol of benzaldehyde and 3.0mmol of malononitrile into a 50mL round-bottom flask respectively, adding 20mL of tetrahydrofuran, adding meso-TPP, 1mmol of triethylamine, adding 0.15mmol of triethylamine, filling air into a reaction bottle, monitoring the reaction by TLC at 50 ℃ (without illumination) for 8h, extracting 3 times with saturated aqueous sodium chloride and ethyl acetate after the reaction is completed, drying with anhydrous sodium sulfate, obtaining a crude product by reduced pressure distillation, and then purifying by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain the compound 1 with the yield of less than 10%.

Comparative example 4

This embodiment provides, as a comparative example of the present invention, a process for producing a polysubstituted hydrogenated benzocycloether derivative, compound 1: the specific steps of the 6-amino-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile are as follows:

1.0mmol of benzaldehyde and 3.0mmol of malononitrile are respectively added into a 50mL round-bottom flask, 20mL of tetrahydrofuran is added, meso-TPP is added, 1mmol percent of triethylamine is added, 0.15mmol of triethylamine is added, air is filled into a reaction bottle, blue light irradiation is carried out for 8h at 50 ℃, the reaction is monitored by TLC, after the reaction is completed, saturated sodium chloride aqueous solution and ethyl acetate are used for extraction for 3 times, the mixture is dried by anhydrous sodium sulfate, a crude product is obtained by reduced pressure distillation, and then the crude product is purified by column chromatography (petroleum ether/ethyl acetate ═ 6: 1) to obtain a compound 1, wherein the yield is 50 percent.

Example 6

Compound 2-compound 45 was prepared using the procedure in example 1.

The compound 26-amino-4- (4-chlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 248.1-249.9 ℃; yield of 81 percent; IR (KBr, v)_max,cm^-1):3352,3288,3215,2933,2862,2223,1664,1634,1495,1394,1094,1057,1024,964,840,742.¹H NMR(600MHz,DMSO-d₆)δ:7.61(d,J＝8.6Hz,2H,NH₂),7.56(d,J＝8.6Hz,2H,ArH),7.46(s,2H,ArH),4.37(d,J＝5.0Hz,1H,OCH),3.86(td,J＝8.2,6.3Hz,1H,OCH _αH_β),3.72(d,J＝12.8Hz,1H,ArCH),3.62(td,J＝8.8,5.8Hz,1H,OCH_α H _β),2.98(dddd,J＝13.0,7.7,5.0,1.9Hz,1H,CH),2.05(dtd,J＝12.9,8.5,6.4Hz,1H,CH _αH_β),1.25(dtd,J＝12.9,8.5,6.4Hz,1H,CH_α H _β).；¹³C NMR(151MHz,DMSO-d₆)δ:148.37,134.50,134.12,129.25,118.58,112.47,112.35,75.23,74.78,65.94,46.17,43.10,37.49,30.18.HRMS(TOF-ESI⁺):m/z calcd for C₁₇H₁₃ClN₄ONa[M+Na]⁺,347.0670,found,347.0667。

The compound 36-amino-4- (p-tolyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

White solid: mp is 189.9-191.5 ℃; 85% of yield; IR (KBr, v)_max,cm^-1)::3351,3300,3216,2933,2882,2221,1666,1635,1518,1460,1391,1291,1187,1068,1029,963,903,699.¹H NMR(600MHz,DMSO-d₆)δ:7.44(d,J＝7.0Hz,4H,NH₂,and ArH),7.27(d,J＝7.9Hz,2H,ArH),4.35(d,J＝5.0Hz,1H,OCH),3.85(td,J＝8.2,6.2Hz,1H,OC _αHH_β),3.61(td,J＝8.8,5.7Hz,1H,OCH_α H _β),3.53(d,J＝12.8Hz,1H,ArCH),2.96(dddd,J＝13.0,7.6,5.1,1.9Hz,1H,CH_αH_β),2.34(s,3H,CH₃),2.08–1.99(m,1H,CH),1.27(dddd,J＝14.8,12.8,6.3,3.5Hz,1H,CH_{α β}H).¹³C NMR(151MHz,DMSO-d₆)δ148.63,139.04,132.02,129.77,118.65,112.65,112.54,75.17,74.85,65.92,46.77,43.39,37.62,30.19,21.19；.HRMS(TOF-ESI⁺):m/z calcd for C₁₈H₁₇N₄O[M+H]⁺,305.1397；found,.305.1395。

The compound 46-amino-4- (2-chlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 189.6-190.9 ℃; yield: 89% IR (KBr, v)_max，cm^-1)：3461，3332，3209，2959，2895，2205，1643，1477，1441，1301，1280，1248，1124，1032，1007，952，925，847，742，684，651.¹H NMR(600MHz，DMSO－d₆)δ：7.76(dd，J＝7.9，1.6Hz，1H，ArH)，7.65(dd，J＝8.0，1.4Hz，1H，ArH)，7.59–7.53(m，3H，ArH and NH₂)，7.50(dd，J＝7.7，1.7Hz，1H，ArH)，4.38(d，J＝4.9Hz，1H，OCH)，4.05(d，J＝12.7Hz，1H，ArCH)，3.87(td，J＝8.3，6.1Hz，1H，OCH _α H_β)，3.65(td，J＝8.9，5.9Hz，1H，OCH_α H _β)，3.02(dddd，J＝12.8，7.9，4.9，1.9Hz，1H，CH _αH_β)，2.04(dtd，J＝13.4，8.5，6.2Hz，1H，CH)，1.16(dddd，J＝13.6，8.0，5.9，1.8Hz，1H，CH_αH _β ).；¹³C NMR(151MHz，DMSO－d₆)δ：148.70，136.08，132.41，131.37，130.61，129.59，128.69，118.47，112.27，111.78，75.00，74.96，66.13，42.90，41.99，38.55，29.98.；HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃ClN₄ONa[M+Na]⁺，347.0670，found，347.0667。

The compound 56-amino-4- (3-chlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 244.2 to 246.3 ℃; yield: 87 percent; IR (KBr, v)_max，cm^-1)：3439，3344，3281，3236，2934，2885，2856，2210，1657，1616，1479，1390，1081，1047，1004，798，763，620.¹H NMR(600MHz，DMSO－d₆)δ：7.67(d，J＝2.0Hz，1H，ArH)，7.59–7.55(d，1H，ArH)，7.53(dd，J＝5.0，2.1Hz，2H，ArH)，7.48(s，2H，NH₂)，4.36(d，J＝5.0Hz，1H，OCH)，3.87(td，J＝8.2，6.4Hz，1H，OC _αHH_β)，3.74(d，J＝12.9Hz，1H，ArCH)，3.62(td，J＝8.8，5.7Hz，1H，OCH_α H _β)，3.01(dddd，J＝13.0，7.6，5.0，1.9Hz，1H，CH _αH_β)，2.07(dtd，J＝13.0，8.5，6.4Hz，1H，CH)，1.27(dddd，J＝13.7，11.7，5.7，2.9Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：148.31，137.58，133.78，131.08，129.70，118.58，112.40，112.32，75.21，74.75，65.96，46.23，43.03，37.39，30.20.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃ClN₄ONa[M+Na]⁺，347.0670，found，347.0667。

The compound 66-amino-4- (o-tolyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

White solid: and Mp: 155.6-156.8 ℃; yield: 88 percent; IR (KBr, v)_max，cm^-1)：3462，3334，3209，2964，2929，2205，1643，1493，1462，1391，1028，960，925，732.¹H NMR(600MHz，DMSO－d₆)δ：7.59(d，J＝7.5，1.2Hz，1H，ArH)，7.58–7.55(m，1H)，7.53(dd，J＝5.0，2.1Hz，2H，ArH)，7.53(7.48(s，2H，NH₂)，4.36(d，J＝5.0Hz，1H，OCH)，3.89(td，J＝8.3，6.2Hz，1H，OC _αHH_β)，3.70(d，J＝12.6Hz，1H，ArCH)，3.63(td，J＝8.9，5.9Hz，1H，OCH_α H _β)，3.01(dddd，J＝13.0，7.6，5.0，1.9Hz，1H，CH _αH_β)，2.40(s，3H，CH₃)，2.07(dtd，J＝13.0，8.5，6.4Hz，1H，CH)，1.27(dddd，J＝13.7，11.7，5.7，2.9Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：149.09，138.99，133.54，131.55，129.22，127.56，127.23，118.69，112.67，112.46，75.09，74.95，66.12，42.48，42.19，38.90，30.00，20.17.HRMS(TOF－ESI⁺)：m/z calcd for C₁₈H₁₇N₄O[M+H]⁺，305.1397；found，.305.1398.

The compound 76-amino-4- (m-tolyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

White solid: and Mp: 233.0 to 234.6 ℃; yield:90 percent; IR (KBr, v)_max，cm^-1)：3417，3350，3280，3242，2931，2875，2207，1660，1616，1490，1391，1132，1041，1001，951，728.¹H NMR(600MHz，DMSO－d₆)δ：7.44(s，2H，NH₂)，7.38–7.32(m，3H，ArH)，7.26(dq，J＝6.5，2.3Hz，1H，ArH)，4.36(d，J＝5.0Hz，1H，OCH)，3.86(td，J＝8.1，6.3Hz，1H，OC _αHH_β)，3.61(td，J＝8.8，5.8Hz，1H，OCH_α H _β)，3.52(d，J＝12.8Hz，1H，ArCH)，2.97(dddd，J＝13.1，7.5，5.0，1.9Hz，1H，CH _αH_β)，2.34(s，3H，CH₃)，2.04(dtd，J＝15.1，7.3，2.2Hz，1H)，CH)，1.28(dddd，J＝11.4，8.0，5.8，2.9Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：148.64，138.35，135.01，130.25，129.07，118.66，112.60，112.51，75.15，74.82，65.93，47.00，43.27，37.62，30.22，21.55.HRMS(TOF－ESI⁺)：m/z calcd for C₁₈H₁₇N₄O[M+H]⁺，305.1397；found，.305.1398。

The compound 86-amino-4- (2-bromophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 232.6-233.9 ℃; yield: 84%; IR (KBr, v)_max，cm^-1)：33460，3335，3208，2959，2898，2202，1640，1475，1445，1300，1284，1241，1122，1031，1002，951，924，847，745，682，659.¹H NMR(600MHz，DMSO－d₆)δ：7.81(dd，J＝8.1，1.3Hz，1H，ArH)，7.74(dd，J＝7.9，1.6Hz，1H，ArH)，7.62–7.56(m，3H，ArH and NH₂)，7.41(dd，J＝7.7，1.6Hz，1H，ArH)，4.38(d，J＝4.9Hz，1H，OCH)，4.06(d，J＝12.6Hz，1H，ArCH)，3.88(td，J＝8.3，6.2Hz，1H，OC _αHH_β)，3.67(td，J＝8.9，5.8Hz，1H，OCH_α H _β)，3.02(dddd，J＝9.8，8.0，4.8，1.8Hz，1H，CH _αH_β)，2.04(dtd，J＝14.1，8.6，6.3Hz，1H，CH)，1.17(dddd，J＝13.6，7.9，5.8，1.9Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：148.73，134.07，133.99，131.66，129.61，129.26，127.57，118.48，112.30，111.73，75.01，74.91，66.18，45.55，41.96，38.77，29.92.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃BrN₄ONa[M+Na]⁺，391.0165，found，391.0160。

The compound 96-amino-4- (4-bromophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 184.2-185.9 ℃; yield: 80 percent; IR (KBr, v)_max，cm^-1)：3437，3350，3216，2957，2882，2212，1654，1493，1390，1283，1251，1137，1074，1022，957，921，838，775，734，674，605.¹H NMR(600MHz，DMSO－d₆)δ：7.70(d，J＝8.5Hz，2H，ArH)，7.54(d，J＝8.6Hz，2H，ArH)，7.47(s，2H，NH₂)，4.36(d，J＝5.0Hz，1H，OCH)，3.86(td，J＝8.1，6.3Hz，1H，OC _αHH_β)，3.71(d，J＝12.9Hz，1H，ArCH)，3.62(td，J＝8.7，5.8Hz，1H，OCH_α H _β)，2.97(dddd，J＝13.0，7.7，5.0，1.8Hz，1H，CH _αH_β)，2.05(ddt，J＝10.6，8.3，4.3Hz，1H，CH)，1.25(dddd，J＝15.1，5.5，1.8Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：148.36，134.54，132.19，123.18，118.60，112.46，112.35，75.18，74.77，65.95，46.20，43.02，37.41，30.18.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃BrN₄ONa[M+Na]⁺，391.0165，found，391.0158.

The compound 106-amino-4- (3-bromophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

White solid: and Mp: 235.8-236.9 ℃; yield:81 percent; IR (KBr, v)_max，cm^-1)：3441，3344，3277，3237，2950，2886，2854，2210，1656，1616，1571，1476，1388，1288，1244，1180，1049，1003，949，785，763.¹H NMR(600MHz，DMSO－d₆)δ：7.81(t，J＝1.9Hz，1H，ArH)，7.66(ddd，J＝8.0，2.1，1.0Hz，1H，ArH)，7.61(dt，J＝7.8，1.3Hz，1H，ArH)，7.51–7.43(m，3H，ArH and NH₂)，4.36(d，J＝5.1Hz，1H，OCH)，3.87(td，J＝8.1，6.3Hz，1H，OC _αHH_β)，3.73(d，J＝12.9Hz，1H，ArCH)，3.62(td，J＝8.7，5.7Hz，1H，OCH_α H _β)，3.01(dddd，J＝13.1，7.5，5.0，1.9Hz，1H，CH _αH_β)，2.06(dtd，J＝12.9，8.5，6.4Hz，1H，CH)，1.26(dddd，J＝13.8，11.8，5.7，3.0Hz，1H，CH_{α β}H).¹³C NMR(151MHz，DMSO－d₆)δ：148.31，137.81，132.60，131.33，122.34，118.59，112.39，112.31，75.18，74.75，65.96，46.16，43.06，37.38，30.21.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃BrN₄ONa[M+Na]⁺，391.0165，found，391.0169。

The compound 116-amino-4- (3, 4-dichlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

White solid: and Mp: 208.9 to 210.5 ℃; yield: 83 percent; IR (KBr, v)_max，cm^-1)：3404，3347，3287，3243，2962，2873，2211，1656，1617，1476，1386，1263，1191，1135，1039，1008，955，771.¹H NMR(600MHz，DMSO－d6)7.90(d，J＝2.1Hz，1H，ArH)，7.79(d，J＝8.4Hz，1H，ArH)，7.61(dd，J＝8.4，2.2Hz，1H，ArH)，7.50(s，2H，NH₂)，4.36(d，J＝5.1Hz，1H，OCH)，3.87(td，J＝8.1，6.3Hz，1H，OCH_αH_β)，3.82(d，J＝12.9Hz，1H，ArCH)，3.63(td，J＝8.7，5.7Hz，1H，OCH_αH_β)，3.06–2.97(m，1H，CH_αH_β)，2.07(dtd，J＝13.1，8.5，6.5Hz，1H，CH)，1.28(dddd，J＝13.3，7.7，5.6，1.9Hz，1H，CH_αH_β).¹³C NMR(600MHz，DMSO－d6)δ：148.14，136.23，132.62，131.88，131.62，131.44，130.23，118.53，112.33，112.20，75.23，74.71，65.97，45.62，42.91，37.28，30.19..HRMS(TOF－ESI+)：m/z calcd for C₁₇H₁₂Cl₂N₄ONa[M+Na]+，381.0280，found，381.0285。

The compound 126-amino-4- (2, 3-dichlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 249.1-250.7 ℃; yield:81 percent; IR (KBr, v)_max，cm^-1)：3383，3331，3287，3192，2943，2886，2218，1667，1621，1424，1396，1248，1157，1035，1001，955，932，739，671.¹H NMR(600MHz，DMSO－d6)δ：7.80(dd，J＝8.0，1.4Hz，1H，ArH)，7.76(dd，J＝8.0，1.5Hz，1H，ArH)，7.64–7.57(m，3H，ArH and NH₂)，4.38(d，J＝4.9Hz，1H，OCH)，4.14(d，J＝12.6Hz，1H，ArCH)，3.87(td，J＝8.3，6.1Hz，1H，OCH_αH_β)，3.66(td，J＝8.9，5.9Hz，1H，OCH_αH_β)，3.08–2.98(m，1H，CH_αH_β)，2.05(dtd，J＝14.2，8.6，6.2Hz，1H，CH)，1.17(dddd，J＝13.7，8.0，5.8，1.8Hz，1H，CH_αH_β).¹³C NMR(151MHz，DMSO－d6)δ：148.55，135.00，134.25，133.22，132.06，129.47，128.29，118.41，112.07，111.71，74.99，74.94，66.16，43.85，41.90，38.67，29.96.HRMS(TOF－ESI+)：m/z calcd for C₁₇H₁₂Cl₂N₄ONa[M+Na]+，381.0280，found，381.0275。

The compound 136-amino-4- (2-ethynylphenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 219.3-220.9 ℃; yield: 79 percent; IR (KBr, v)_max，cm^-1)：3461，3334，3264，3210，2959，2893，2205，1642，1485，1399，1251，1032，929，852，763，664.¹H NMR(600MHz，Acetone－d6)δ7.76–7.68(m，2H，ArH)，7.34–7.26(m，2H，ArH)，6.75(s，2H，NH₂)，4.44(d，J＝5.1Hz，1H，OCH)，3.94(td，J＝8.4，5.9Hz，1H，OCH_αH_β)，3.71(td，J＝8.8，6.1Hz，1H，OCH_αH_β)，3.64(d，J＝12.8Hz，1H，ArCH)，3.13(dddd，J＝13.1，7.8，5.2，2.1Hz，1H，CH_αH_β)，2.94(s，1H，CCH)，2.23–2.16(m，1H，CH)，1.48(dddd，J＝13.1，8.1，6.1，2.1Hz，1H，CH_αH_β)¹³C NMR(151MHz，Acetone－d6)δ：147.96，136.65，133.34，129.79，129.23，127.29，125.16，116.98，112.09，111.30，84.78，80.65，77.84，74.78，66.12，44.22，42.05，38.90，29.79.HRMS(TOF－ESI⁺)：m/z calcd for C₁₉H₁₅N₄O[M+H]+，315.1240；found，315.1239。

The compound 146-amino-4- (3-cyanophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 223.2 to 224.9 ℃; yield: 80 percent; IR (KBr, v)_max，cm^-1)：3395，3339，3272，3237，2962，2933，2872，2237，2205，1658，1619，1396，1066，1033，1001，962，690，615.¹H NMR(600MHz，DMSO－d6)δ：8.10(d，J＝1.8Hz，1H，ArH)，7.98–7.93(m，2H，ArH)，7.72(t，J＝7.9Hz，1H，ArH)，7.52(s，2H，NH ₂ )，4.37(d，J＝5.0Hz，1H，OCH)，3.90–3.81(m，2H，ArCH and OCH _α H _β )，3.63(td，J＝8.8，5.7Hz，1H，OCH _α H _β )，3.13–3.05(m，1H，CH _α H _β )，2.07(dtd，J＝13.0，8.5，6.4Hz，1H，CH)，1.23(dddd，J＝13.4，7.8，5.8，1.9Hz，1H，CH _α H _β ).¹³C NMR(151MHz，DMSO－d6)δ：148.13，136.75，133.48，130.53，118.89，118.54，112.34，112.15，74.71，65.97，60.21，46.09，42.95，40.15，40.01，39.87，37.10，30.20.HRMS(TOF－ESI⁺)：m/z calcd for C₁₈H₁₄N₅O[M+H]+，316.1193；found，316.1198。

The compound 156-amino-4- (3- (trifluoromethyl) phenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 252.9-254.1 ℃; yield: 80 percent; IR (KBr, v)_max，cm^-1)：3431，3356，3287，3218，2945，2871，2212，1660，1455，1395，1332，1251，1170，1132，1097，1033，957，929，905，813，727，712，667，605.¹H NMR(600MHz，DMSO－d6)δ：7.98(s，1H，ArH)，7.92(d，J＝8.0Hz，1H，ArH)，7.84(dd，J＝7.5，1.7Hz，1H，ArH)，7.74(t，J＝7.8Hz，1H，ArH)，7.50(s，2H，NH₂)，4.38(d，J＝5.1Hz，1H，OCH)，3.92–3.86(m，2H，ArCH and OCH_αH_β)，3.63(td，J＝8.7，5.8Hz，1H，OCH_αH_β)，3.09(dddd，J＝13.2，7.6，5.1，1.9Hz，1H，CH_αH_β)，2.07(dtd，J＝12.9，8.5，6.3Hz，1H，CH)，1.24(dddd，J＝13.3，7.8，5.7，1.9Hz，1H，CH_αH_β).¹³C NMR(151MHz，DMSO－d6)δ：148.20，136.51，130.36，129.97，126.46(d，J_C－F＝4.2Hz).，125.35(d，J_C－F＝272.2Hz).，123.55，118.58，112.37，112.25，75.24，74.75，65.99，46.28，43.07，37.24，30.22.¹⁹F NMR(565MHz，DMSO－d6)δ－61.07，－61.15，－61.30.HRMS(TOF－ESI⁺)：m/z calcd for C₁₈H₁₄F₃N₄O[M+H]+，359.1114；found，.359.1104.

The compound 166-amino-4- (4-fluorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 202.6-204.3 ℃; yield: 70 percent; IR (KBr, v)_max，cm^-1)：3352，3292，3216，2933，2886，2224，1666，1634，1514，1394，1294，1237，1164，1026，961，917，845，660.1H NMR(600MHz，Acetone－d6)δ：7.63–7.54(m，2H，ArH)，7.20–7.13(m，2H，ArH)，6.60(s，2H，NH₂)，4.30(d，J＝5.2Hz，1H，OCH)，3.81(td，J＝8.3，6.0Hz，1H，OCH_αH_β)，3.58(td，J＝8.8，6.1Hz，1H，OCH_αH_β)，3.50(d，J＝12.8Hz，1H，ArCH)，2.99(dddd，J＝13.1，7.7，5.1，2.1Hz，1H，CH_αH_β)，2.06(dtd，J＝13.1，8.6，6.0Hz，1H，CH)，1.34(dddd，J＝13.1，8.2，6.1，2.1Hz，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：163.23(d，J_C－F＝247.6Hz)，147.65，130.83(d，J＝3.0)，117.07，115.80，115.66，111.96，111.84，77.73，74.55，65.85，46.67，43.15，37.92，29.86.¹⁹F NMR(565MHz，Acetone－d6)δ－113.85.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₄FN₄O[M+H]+，309.1146；found，.309.1140。

Compound 176-amino-4- (3-nitrophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 236.2-237.8 ℃; yield: 89 percent; IR (KBr, v)_max，cm^-1)：3439，3354，3283，2931，2861，2213，1657，1616，1534，1382，1355，1052，717，607.¹H NMR(600MHz，Acetone－d6)δ：8.45(t，J＝2.0Hz，1H，ArH)，8.26(ddd，J＝8.2，2.3，1.0Hz，1H，ArH)，8.02(dt，J＝7.7，1.4Hz，1H，ArH)，7.74(t，J＝8.0Hz，1H，ArH)，6.67(s，2H，NH₂)，4.35(d，J＝5.1Hz，1H，OCH)，3.85(td，J＝8.3，6.0Hz，1H，OCH_αH_β)，3.80(d，J＝12.8Hz，1H，ArCH)，3.60(td，J＝8.8，6.1Hz，1H，OCH_αH_β)，3.14(dddd，J＝13.1，7.7，5.1，2.1Hz，1H，CH_αH_β)，2.18–2.07(m，1H，CH)，1.37(dddd，J＝13.2，8.2，6.1，2.1Hz，1H，CH_αH_β).¹³C NMR 151MHz，Acetone－d6)δ：148.55，147.28，136.93，130.46，124.30，116.96，111.75，111.61，77.89，74.50，65.92，46.78，42.78，37.69，29.90.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₄N₅O₃[M+Na]+，358.0911，found，358.0912。

The compound 186-amino-4- (2, 3-dimethylphenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 230.9-232.1 ℃; yield:90 percent; IR (KBr, v)_max，cm^-1)：3351，3216，2933，2882，2221，1757，1666，1635，1518，1480，1391，1291，1187，1136，1088，1029，983，903，669 ¹H NMR(600MHz，Acetone－d6)δ：7.4(dd，J＝6.6，2.7Hz，1H，ArH)，7.15–7.10(m，2H，ArH)，6.57(s，2H，NH₂)，4.31(d，J＝5.1Hz，1H，OCH)，3.86(d，J＝12.4Hz，1H，ArCH)，3.81(td，J＝8.2，6.4Hz，1H，OCH_αH_β)，3.58(td，J＝8.8，6.1Hz，1H，OCH_αH_β)，2.98(dddd，J＝12.9，7.7，5.1，2.1Hz，1H，CH_αH_β)，2.27(s，3H，CH₃)，2.23(s，3H，CH₃)，1.99(dddd，J＝13.3，8.0，7.1，5.3Hz，1H，CH)，1.24(dddd，J＝13.2，8.2，6.1，2.1Hz，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：148.39，137.77，137.49，133.01，130.46，126.05，125.07，117.16，112.21，111.92，82.17，74.89，69.99，42.61，42.02，39.28，29.84，20.50，15.05.19F NMR(565MHz，Chloroform－d)δ：－113.73.HRMS(TOF－ESI⁺)：m/z calcd for C₁₉H₁₉N₄O[M+H]+，319.1553；found，.319.1549。

The compound 196-amino-4- (2, 4-dichlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 159.9 to 261.2 ℃; yield: 89 percent; IR (KBr, v)_max，cm^-1)：3383，3338，3198，2961，2885，2217，1665，1620，1599，1476，1392，1139，1107，1033，1001，926，872，827，792 ¹H NMR(600MHz，Acetone－d6)δ：7.73(d，J＝8.5Hz，1H，ArH)，7.60(d，J＝2.2Hz，1H，ArH)，7.50(dd，J＝8.5，2.2Hz，1H，ArH)，6.67(s，2H，NH₂)，4.34(d，J＝5.0Hz，1H，OCH)，4.08(d，J＝12.6Hz，1H，ArCH)，3.85(td，J＝8.4，6.1Hz，1H，OCH_αH_β)，3.62(td，J＝8.8，6.0Hz，1H，OCH_αH_β)，3.01(dddd，J＝12.9，7.6，5.1，2.1Hz，1H，CH_αH_β)，2.06(dddd，J＝13.3，8.9，8.1，6.1Hz，1H，CH)，1.25(dddd，J＝13.7，8.1，6.0，2.1Hz，1H，CH_αH_β).13C NMR(151MHz，Acetone－d6)δ：147.63，137.22，135.54，131.42，130.48，129.86，128.41，116.86，111.74，111.15，77.78，74.71，66.04，42.46，41.73，38.77，29.75.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₂Cl₂N₄ONa[M+Na]+，381.0280，found，381.0279。

The compound 206-amino-4- (2, 6-difluorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 230.9-232.6 ℃; yield: 75 percent; IR (KBr, v)_max，cm^-1)：3345，3295，3213，2930，2225，1669，1630，1588，1470，1392，1273，1234，1064，1026，992，959，921，795，751.¹H NMR(600MHz，Acetone－d6)δ：7.51(tt，J＝8.5，6.3Hz，1H，ArH)，7.12–7.06(m，2H，ArH)，6.69(s，2H，NH₂)，4.32(d，J＝4.9Hz，1H，OCH)，3.85(td，J＝8.5，5.9Hz，1H，OCH_αH_β)，3.81(d，J＝12.8Hz，1H，ArCH)，3.64(td，J＝9.0，6.0Hz，1H，OCH_αH_β)，3.30(dddd，J＝12.9，8.2，5.0，1.8Hz，1H，CH_αH_β)，2.21–2.12(m，1H，CH)，1.44–1.36(m，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：163.28(dd，J_C－F＝9.06，4.53Hz)，162.98，161.65(dd，J_C－F＝9.06，4.53Hz)，161，32，147.98，132.60(t，J_C－F＝11.1Hz)，116.92，113.16(dd，J_C－F＝23.3，3.6Hz)，113.03，112.24(dd，J_C－F＝23.9，3.5Hz)，112.08，111.71，111.45，109.98，77.57，74.75，65.97，41.24，40.06(t，J_C－F＝3.5Hz)，36.89(d，J_C－F＝7.9Hz)，29.37.¹⁹F NMR(565MHz，Chloroform－d)δ－108.73，－114.77..HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃F₂N₄O[M+H]+，327.1052；found，.327.1055。

The compound 216-amino-4- (2, 5-dichlorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 263.7-264.9 ℃; yield: 89 percent; IR (KBr, v)_max，cm^-1)：3456，3329，3207，2930，2903，2205，1642，1466，1392，1102，1027，924，826.¹H NMR ¹H NMR(600MHz，Acetone－d6)δ：7.74(d，J＝2.5Hz，1H，ArH)，7.55(d，J＝8.6Hz，1H，ArH)，7.45(dd，J＝8.7，2.5Hz，1H，ArH)，6.69(s，2H，NH₂)，4.34(d，J＝5.1Hz，1H，OCH)，4.10(d，J＝12.6Hz，1H，ArCH)，3.86(td，J＝8.4，6.1Hz，1H，OCH_αH_β)，3.63(td，J＝8.9，6.0Hz，1H，OCH_αH_β)，3.07(dddd，J＝12.9，8.1，5.1，2.1Hz，1H，CH_αH_β)，2.10(dddd，J＝13.3，9.0，8.1，6.1Hz，1H，CH)，1.27(dddd，J＝13.6，8.1，6.0，2.1Hz，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：147.54，134.88，134.37，133.44，131.74，130.92，129.21，116.85，111.70，111.07，77.80，74.69，66.07，42.82，41.67，38.70，29.80.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₂Cl₂N₄ONa[M+Na]+，381.0280，found，381.0275。

The compound 226-amino-4-butyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 200.0-201.1 ℃; yield: 65% IR (KBr, v)_max，cm^-1)：3342，3262，3232，2935，2869，2205，1652，1596，1463，1419，1317，1248.¹H NMR(600MHz，Acetone－d6)δ：6.46(s，2H，NH₂)，4.14(d，J＝5.5Hz，1H，OCH)，3.84(td，J＝8.2，5.9Hz，1H，OCH_αH_β)，3.60(td，J＝8.5，6.2Hz，1H，OCH_αH_β)，2.31(ddq，J＝11.8，5.5，2.7Hz，1H，CH)，2.21(dtd，J＝12.9，8.3，6.0Hz，1H，CH)，2.12(dt，J＝12.0，4.7Hz，1H，CH)，1.90–1.84(m，1H，CH)，1.75–1.65(m，2H，CH₂)，1.57–1.49(m，2H，CH₂)，1.30(ddt，J＝14.9，7.4，4.0Hz，2H，CH₂)，0.83(m，3H，CH₃)；¹³C NMR(151MHz，Acetone－d6)δ：147.33，116.90，113.01，112.14，78.16，74.21，65.88，41.90，41.39，39.70，31.42，30.34，29.71，22.66，13.13；HRMS(TOF－ESI⁺)：m/z calcd for C₁₅H₁₉N₄O[M+H]+，270.1553；found，270.1553。

The compound 236-amino-4-cyclohexyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 160.0-161.3 ℃; yield: 67%; IR (KBr, v)_max，cm^-1)：3349，3216，2939，2860，2210，1640，1451，1385，1069，1031.¹H NMR(600MHz，Acetone－d6)δ：6.51(s，2H，NH₂)，4.67(d，J＝7.0Hz，1H，OCH)，3.84(dd，J＝8.4，6.0Hz，2H，OCH₂)，2.94(dddd，J＝10.9，8.6，7.0，3.7Hz，1H，CH)，2.64(dd，J＝8.8，3.7Hz，1H，CH)，2.19(dd，J＝12.2，5.1Hz，2H，CH₂)，1.93–1.87(m，4H，CH₂)，1.75–1.68(m，2H，CH₂)，1.41(d，J＝3.1Hz，1H，CH)，1.40–1.37(m，2H，CH₂)，1.29(d，J＝2.6Hz，1H，CH)1.29–1.24((dd，J＝3.6，2.6Hz，2H，CH₂).¹³C NMR(151MHz，Acetone－d6)δ144.80，116.34，114.66，112.97，82.03，73.78，65.85，45.36，41.64，40.28，36.73，32.33，29.97，25.90，25.76，23.79.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₂₁N₄O[M+H]+，297.1710；found，297.1707。

The compound 246-amino-4- (2-chloro-6-fluorophenyl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -trinitrile

A white solid; and Mp: 202.9-204.0 ℃; yield: 76%; IR (KBr, v)_max，cm^-1)：3464，3341，3214，2956，2894，2209，1646，1612，1581，1458，1390，1248，1069，1029，903，792.¹H NMR(600MHz，Acetone－d6)δ：7.47(td，J＝8.2，5.7Hz，1H，ArH)，7.39(dt，J＝8.1，1.1Hz，1H，ArH)，7.22(ddd，J＝11.5，8.4，1.3Hz，1H，ArH)，6.69(s，2H，NH₂)，4.34(d，J＝4.8Hz，1H，OCH)，4.16(d，J＝12.6，Hz，1H，ArCH)，3.85(td，J＝8.4，6.3Hz，1H，OCH_αH_β)，3.66(td，J＝8.9，5.7Hz，1H，OCH_αH_β)，3.31(dtd，J＝14.7，5.0，2.0Hz，1H，CH_αH_β)，2.13(dddd，J＝13.3，9.1，8.0，6.3Hz，1H，CH)，1.32(dddd，J＝13.5，7.9，5.7，1.9Hz，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：162.51(d，J_C－F＝252.2Hz)，161.96，148.42，137.74(d，J＝6.0Hz)，132.35(d，J＝10.6Hz)，126.66(d，J＝3.0Hz)，119.72(d，J＝15.1Hz)，116.94，116.32(d，J＝24.2Hz)，111.48(d，J＝28.7Hz)，77.45，74.93，66.13，43.75，40.62，37.38，29.40.HRMS(TOF－ESI⁺)：m/z calcd for C₁₇H₁₃ClFN₄O[M+H]+，343.0756；found，343.0758。

The compound 256-amino-4- (naphthalen-2-yl) -2,3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile

A white solid; and Mp: 225.7-227.1 ℃; yield: 89 percent; IR (KBr, v)_max，cm^-1)：3354，3211，3066，2933，2208，1685，1621，1396，1258，1030.¹H NMR(600MHz，Acetone－d6)δ：8.08(d，J＝1.9Hz，1H，ArH)，7.92(d，J＝8.5Hz，1H，ArH)，7.88–7.84(m，2H，ArH)，7.65(dd，J＝8.6，1.9Hz，1H，ArH)，7.48–7.44(m，2H，ArH)，6.61(s，2H，NH₂)，4.36(d，J＝5.1Hz，1H，OCH)，3.84(td，J＝8.4，6.0Hz，1H，OCH_αH_β)，3.63(d，J＝12.5Hz，1H，ArCH)，3.61–3.57(m，1H，OCH_αH_β)，3.16(dddd，J＝13.1，7.7，5.1，2.1Hz，1H，CH_αH_β)，2.12–2.04(m，1H，CH)，1.40(dddd，J＝13.7，8.2，6.1，2.1Hz，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：147.84，133.75，133.28，132.15，128.66，128.20，127.73，126.94，126.69，117.09，112.07，112.02，77.92，74.66，65.93，47.70，43.21，37.98，29.99.HRMS(TOF－ESI⁺)：m/z calcd for C₂₁H₁₆N₄ONa[M+Na]+，363.1216，found，363.1216。

The compound 267-amino-5- (4-chlorophenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile

A white solid; and Mp: 249.7-251.0 ℃; yield: 84%; IR (KBr, v)_max，cm^-1)：3405，3341，3278，3238，2955，2861，2206，1654，1621，1496，1388，1094，1059，1034，889，836，764.¹H NMR(600MHz，Acetone－d6)δ：7.64–7.40(m，4H，ArH)，6.67(s，2H，NH₂)，4.12(d，J＝2.6Hz，1H，OCH)，3.96(d，J＝12.3Hz，1H，ArCH)，3.82–3.75(m，1H，OCH_αH_β)，3.39(dtd，J＝12.4，11.4，2.3Hz，1H，OCH_αH_β)，2.37(ddt，J＝12.3，4.9，2.4Hz，1H，CH)，1.67(tt，J＝14.0，4.5Hz，1H，CH_αH_β)，1.53(dt，J＝14.2，3.2Hz，1H，CH_αH_β)，1.26(dtd，J＝13.6，9.3，4.6Hz，1H，CH_αH_β)，1.08–0.98(m，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d6)δ：147.10，134.80，132.60，129.00，117.37，112.37，112.31，80.41，72.37，67.98，44.72，43.63，32.76，24.79，20.06.HRMS(TOF－ESI⁺)：m/z calcd for C₁₈H₁₅ClN₄ONa[M+Na]⁺，361.0827，found，361.0822。

The compound 277-amino-5- (4-methoxyphenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile

A white solid; and Mp: 121.3-122.5 ℃; yield: 80 percent; IR (KBr, v)_max，cm^-1)：3442，3350，3231，2952，2864，2207，1635，1622，1615，1516，1464，1445，1252，1182，1101，1035，938，889，844，838¹H NMR(600MHz，Acetone－d6)δ7.15(d，J＝8.5Hz，2H，ArH)，7.00–6.92(m，2H，ArH)，6.43(s，2H，NH₂)，4.17–4.10(m，2H，OCH，OCH_αH_β)，3.80(s，3H，ArOCH3)，3.66(td，J＝11.8，2.5Hz，1H，OCH_αH_β)，3.33(d，J＝10.1Hz，1H，ArCH)，1.76–1.73(m，1H，CH)，1.70(m，2H，CH₂)，1.49–1.41(m，1H，CH_αH_β)，1.32–1.25(m，1H，CH_αH_β).¹³C NMR(151MHz，Acetone－d₆)δ：159.32，143.46，132.03，129.37，116.62，114.15，112.27，83.05，78.30，68.27，54.66，46.32，41.76，41.69，26.47，24.84.HRMS(TOF－ESI⁺)：m/z calcd for C₁₉H₁₈BrN₄O₂[M+H]⁺，335.1503；found，335.1500。

The compound 287-amino-5- (4-fluorophenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 297-amino-5- (p-tolyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 307-amino-5- (4-nitrophenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 317-amino-5-phenyl-3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -tricarbonitrile.

The compound 327-amino-5- (2, 3-dimethylphenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 337-amino-5-cyclohexyl-3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -tricarbonitrile.

The compound 347-amino-5- (2, 4-dichlorophenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 357-amino-5- (2-ethynylphenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 367-amino-5- (4- (trifluoromethyl) phenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 377-amino-5- (2-chloro-6-fluorophenyl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 386-amino-8-phenyl-2, 3, 8, 8 a-tetrahydrobenzo [ b ] [1, 4] dioxine-5, 7, 7(4aH) -trinitrile.

The compound 396-amino-8- (p-tolyl) -2,3, 8, 8 a-tetrahydrobenzo [ b ] [1, 4] dioxine-5, 7, 7(4aH) -tricarbonitrile.

The compound 406-amino-8- (4-bromophenyl) -2,3, 8, 8 a-tetrahydrobenzo [ b ] [1, 4] dioxine-5, 7, 7(4aH) -tricarbonitrile.

The compound 416-amino-7 a-methyl-4-phenyl-2, 3,3a, 7 a-tetrahydrobenzofuran-5, 5,7(4H) -tricarbonitrile.

The compound 427-amino-5- (naphthalen-2-yl) -3, 4, 4a, 8 a-tetrahydro-2H-chromene-6, 6, 8(5H) -trinitrile.

The compound 436-amino-8- (naphthalen-2-yl) -2,3, 8, 8 a-tetrahydrobenzo [ b ] [1, 4] dioxine-5, 7, 7(4aH) -tricarbonitrile.

The compound 447-amino-6-cyano-5-phenyldiethyl-3, 4, 4a, 5, 6, 8 a-hexahydro-2H-chromene-6, 8-dicarboxylate.

The compound 45 diethyl 6-amino-7-cyano-8-phenyl-2, 3, 4a, 7, 8, 8 a-hexahydrobenzo [ b ] [1, 4] dioxine-5, 7-dicarboxylate.

Compounds 1 to 45 were all white solids.

The invention is not limited to the above alternative embodiments, and any other various forms of products can be obtained by anyone in the light of the present invention, but any changes in shape or structure thereof, which fall within the scope of the present invention as defined in the claims, fall within the scope of the present invention.