A (Z)-nitrogen heterocyclic alkenyl chloride compound and its preparation method and application

Abstract

The present invention discloses a (Z)-nitrogen heterocyclic alkenyl chloride compound and a preparation method and application thereof. The structural formula of the compound is any one of #imgabs0#; wherein R 1 is at least one of a hydrogen atom, an alkyl substituent and an aryl substituent; R 2 is at least one of a hydrogen atom, an alkyl substituent, an aryl substituent, an allyl group, and a propargyl group; n1 is an integer of 1 to 5, and n2 is an integer of 1 to 5. The preparation method of the (Z)-nitrogen heterocyclic alkenyl chloride compound of the present invention adopts a simple non-toxic metal iron salt catalyst and a simple Cl ‑ Reagents, water or heavy water are green, efficient, and easy to mass produce. The obtained compound is a product with a single Z-form structure and can be used for the development of heterocyclic drug molecules.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a (Z)-nitrogen heterocycloalkenyl chloride compound and a preparation method and application thereof. Background Art

[0002] Alkenyl chloride compounds are an important class of synthetic intermediates, which are widely used in the synthesis of diverse important molecular skeletons and widely exist in a variety of natural products and bioactive molecules. At the same time, the structure of alkenyl chloride can also be easily converted into different CC and C-hetero bonds. However, the examples of constructing alkenyl chloride compounds by hydrochlorination of triple bonds with high stereoselectivity are still very limited. Recently, Engle's research group realized the asymmetric hydrochlorination of triple bonds under Pd catalysis through directing groups (J.Am.Chem.Soc.,2017,139,5183-5193). The use of precious metal Pd and the subsequent removal of directing groups have limited the further application of this reaction. The development of more efficient and practical hydrochlorination processes is of great research significance. Since the development of the first deuterium-containing drug molecule, deutetrabenazine (SD-809, J. Med. Chem., 2014, 57, 3595), the research and development of deuterated drugs has recently attracted widespread attention from pharmacologists. The introduction of deuterium into drug molecules and the selective modification of molecules can significantly change the pharmacological activity of drug molecules. In addition, the effect of drug molecules can be monitored by the radioactivity of isotopes, and corresponding exploratory monitoring can also be provided for clinical exploration of the mechanism of action of drug molecules. Therefore, it is of great research significance to develop an effective and simple method to introduce deuterium elements into the molecular structure.

[0003] The hydrogen functionalization cyclization reaction of ene yne compounds is an important means to construct heterocyclic compounds. At present, many metal-catalyzed hydrogen functionalization cyclization reactions of ene yne compounds have been developed, and the catalysts used are often precious metal catalysts such as Ru, Rh, Pd, etc. It is of great research significance to realize the cyclization reaction of ene yne compounds through some cheap, non-toxic, and widely available abundant metal catalysts. At present, there are still very limited examples of hydrogen functionalization of ene yne compounds through cheap metal salt catalysts. It is of great significance to develop green, efficient, and simple cheap metal salt-catalyzed synthesis of (Z)-nitrogen heterocyclic alkenyl chloride compounds. It is of great research significance to selectively introduce deuterium into the molecular structure using deuterated water as a raw material to synthesize deuterium-containing drug molecules. At present, there are still very limited examples of introducing deuterium elements into the molecular structure using deuterated water as a raw material. It is of great significance to develop a green, efficient, and simple catalytic system (using deuterated water as a raw material to introduce deuterium) to synthesize deuterium-substituted heterocyclic compounds. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a (Z)-nitrogen heterocyclic alkenyl chloride compound and a preparation method thereof. The preparation method is simple and efficient, and the obtained compound has a single Z-form structure and can be used for the development of heterocyclic drug molecules.

[0005] The present invention solves the above technical problems through the following technical means:

[0006] A (Z)-azacycloalkenyl chloride compound, the structural formula of which is any one of the following formulas I and II:

[0007]

[0008] Among them, in Formula I and Formula II, R 1 is at least one of a hydrogen atom, an alkyl substituent and an aryl substituent; R 2 is at least one of a hydrogen atom, an alkyl substituent, an aryl substituent, an allyl group, and a propargyl group; n1 is an integer of 1-5, and n2 is an integer of 1-5.

[0009] Preferably, R 1 , R 2 The cycloalkyl group has an integer of 3 to 8 carbon atoms.

[0010] Preferably, R 1 and R 2 wherein the alkyl substituent is a C1-C10 alkyl group; the aryl substituent is phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-hydroxymethylphenyl, p-methylphenyl, p-tert-butylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boric acid pinacol ester phenyl, p-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-methoxyphenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl,

[0011]

[0012] At least one of .

[0013] Preferably, the alkyl substituent is one of methyl, ethyl and n-butyl.

[0014] Preferably, in Formula I and Formula II, R 1 is phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-tert-butylphenyl, p-hydroxymethylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boronic acid pinacol ester phenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl, ethyl, n-butyl, hydrogen, One of the2 It is one of methyl and phenyl.

[0015] The present invention also provides a method for preparing the (Z)-nitrogen heterocyclic alkenyl chloride compound, comprising the following steps: mixing an ene yne compound with a metal iron salt catalyst, and then adding water or a dichloromethane solution of heavy water and Cl - Reagents are added and heated to react to obtain the (Z)-azaheterocycloalkenyl chloride compound.

[0016] Preferably, the structural formula of the enyne compound is Among them, R 1 is at least one of a hydrogen atom, an alkyl substituent and an aryl substituent; R 2 is at least one of a hydrogen atom, an alkyl substituent, an aryl substituent, an allyl group, and a propargyl group; n1 is an integer of 1-5, and n2 is an integer of 1-5.

[0017] Preferably, in the structural formula of the enyne compound, R 1 and R 2 wherein the alkyl substituent is an alkyl group having 1 to 10 carbon atoms; the aryl substituent is phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-hydroxymethylphenyl, p-methylphenyl, p-tert-butylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boric acid pinacol ester phenyl, p-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-methoxyphenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl, At least one of .

[0018] Preferably, in the structural formula of the enyne compound, R 1 is phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-tert-butylphenyl, p-hydroxymethylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boronic acid pinacol ester phenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl, ethyl, n-butyl, hydrogen, One of the 2 It is one of methyl and phenyl.

[0019] Preferably, the Cl - The reagent is at least one of acetyl chloride, benzoyl chloride, and trimethylsilyl chloride TMSCl; the metal iron salt catalyst is a mixture of one or more of Fe(acac)2, Fe(OAc)2, FeCl2, FeCl3, Fe2(SO4)3, and Fe(acac)3; the ene yne compound, Cl -The molar ratio of the reagent to water or heavy water is 1:1-5:1-5; the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 0.5-30:100; the reaction temperature is 20°C-100°C, and the reaction time is 0.1-1 hour.

[0020] Preferably, the enyne compound, Cl - The molar ratio of the reagent to water or heavy water is 1:1.5:1.5; the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 0.5-5:100.

[0021] Preferably, the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 5 to 30:100.

[0022] Preferably, the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 1-20:100.

[0023] Preferably, the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 1:100.

[0024] Preferably, the reaction temperature is 80°C.

[0025] Preferably, the reaction time is 10 minutes.

[0026] Preferably, the preparation method further comprises the step of separating and purifying the product after the heating reaction; the separation and purification method comprises at least one of column chromatography, vacuum distillation and recrystallization.

[0027] The present invention also provides an application of the (Z)-azaheterocycloalkenyl chloride compound in the preparation of heterocyclic drug molecules.

[0028] The present invention also provides a heterocyclic compound prepared by using the (Z)-nitrogen heterocyclic alkenyl chloride compound, the structural formula of which is One of them.

[0029] In the structural formula of the present invention, Ts is p-toluenesulfonyl.

[0030] The advantages of the present invention are:

[0031] 1. The catalyst used in the present invention is cheap, readily available, widely available, low in toxicity, and easy to operate;

[0032] 2. The preparation method of the present invention has a rapid reaction, which greatly reduces the synthesis cost and synthesis cycle;

[0033] 3. The amount of catalyst used in the synthesis method of the present invention can be reduced to 1 mol%, with high catalytic efficiency and good enantioselectivity;

[0034] 4. The synthesis method adopted by the present invention is green and environmentally friendly;

[0035] 5. The method of the present invention is easy to produce on a large scale, and the yield and selectivity can be maintained after amplification;

[0036] 6. The compound synthesized by the present invention is a product of a single Z-form structure and can be used for the development of heterocyclic drug molecules;

[0037] 7. The present invention selectively introduces deuterium elements into specific active sites of molecules by developing new organic chemical reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the H NMR spectrum of the product prepared in Example 2 of the present invention;

[0039] Figure 2 This is the NMR carbon spectrum of the product prepared in Example 2 of the present invention;

[0040] Figure 3 This is the H NMR spectrum of the product prepared in Example 3 of the present invention;

[0041] Figure 4 This is the NMR carbon spectrum of the product prepared in Example 3 of the present invention;

[0042] Figure 5 This is the H NMR spectrum of the product prepared in Example 4 of the present invention;

[0043] Figure 6 The NMR carbon spectrum of the product prepared in Example 4 of the present invention;

[0044] Figure 7 This is the H NMR spectrum of the product prepared in Example 5 of the present invention;

[0045] Figure 8 This is the NMR carbon spectrum of the product prepared in Example 5 of the present invention;

[0046] Fig. 9 This is the H NMR spectrum of the product prepared in Example 6 of the present invention;

[0047] Fig.10 This is the NMR carbon spectrum of the product prepared in Example 6 of the present invention;

[0048] Fig.11 This is the H NMR spectrum of the product prepared in Example 7 of the present invention;

[0049] Fig.12 This is the NMR carbon spectrum of the product prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0051] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0052] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0053] Example 1

[0054] Preparation of Enyne Compounds

[0055] The enyne compounds were synthesized according to the methods reported in the literature (Angew. Chem. Int. Ed.. 2010, 49, 5138; Adv. Synth. Catal. 2015, 357, 3069), and the relevant experimental steps were basically consistent with the methods reported in the literature; among them, The preparation method comprises the following steps:

[0056]

[0057] In an ice-water bath at 0°C, K2CO3 (38.0 mmol) and allyl bromide (40.0 mmol) were added to a solution of Ts (p-toluenesulfonyl) protected propargylamine (25.0 mmol) in acetone (25 mL), and the mixture was heated under reflux for 24 hours. The solvent was removed by rotary evaporation, and the obtained solid was dissolved in ethyl acetate, washed with water, extracted, and dried to obtain a crude product, which was directly used in the next step. In a nitrogen atmosphere, iodobenzene (11.0 mmol), Pd(PPh3)2Cl2 (0.2 mmol), and CuI (0.2 mmol) were added to a solution of the obtained crude product (10.0 mmol) in Et3N (20 mL). The mixture was stirred in a nitrogen atmosphere for 16 hours, and the obtained product was washed with water, dried, and separated by column chromatography to obtain the final product.

[0058] Other enyne compounds used in the examples of the present invention were prepared by referring to the above method.

[0059] Example 2

[0060] Preparation of (Z)-Azacycloalkenyl chloride compounds

[0061] Prepare according to the reaction equation shown below:

[0062]

[0063] 1,6-enyne (50mmol) and Fe(acac)3 (0.5mmol) were added into the reactor, and then H2O (75mmol) was dissolved in 10ml of dichloromethane and added into the reactor. Trimethylsilyl chloride (75mmol) was added dropwise in an ice-water bath at 0°C. The mixture was heated to 80°C and stirred for 10 minutes. The reaction was completed and the target product (Z)-azacycloalkenyl chloride was separated by column chromatography with a yield of 91%.

[0064] The NMR spectra of the (Z)-azacycloalkenyl chloride compounds are shown in Figure 2. Figure 1 and Figure 2 As shown, the data is as follows: 1 HNMR(600MHz, CDCl3)δ7.75(d,J=8.3Hz,2H),7.40–7.37(m,2H),7.35–7.31(m ,3H),7.25–7.21(m,2H),4.05(s,2H),3.00(s,2H),2.47(s,3H),0.91(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,141.9,137.9,132.2,129.9,129.2,129.0,128.4,128.2,125.3,63.1,54.0,43.3,26.2,21.8.

[0065] Example 3

[0066] Preparation of (Z)-Azacycloalkenyl chloride compounds

[0067] Prepare according to the reaction equation shown below:

[0068]

[0069] 1,7-enyne (50mmol) and FeCl3 (0.5mmol) were added into the reactor, and H2O (75mmol) was dissolved in 10ml of dichloromethane and added into the reactor. Acetyl chloride (75mmol) was added dropwise in a 0℃ ice-water bath, and the mixture was heated to 40℃. After stirring for 10 minutes, the reaction was completed. The target product (Z)-azacycloalkenyl chloride was separated by column chromatography with a yield of 64%. The NMR spectrum of the structure of the (Z)-azacycloalkenyl chloride was shown in FIG. Figure 3 and Figure 4 shown.

[0070] Example 4

[0071]

[0072] 1,6-enyne (50mmol) and Fe(OAc)2(0.5mmol) were added into the reactor, and then H2O(75mmol) was dissolved in 10ml of dichloromethane and added into the reactor, and benzoyl chloride (75mmol) was added dropwise in a 0℃ ice-water bath, and the mixture was heated to 50℃. After stirring for 10 minutes, the reaction was completed, and the reaction temperature was raised to 100℃. The reaction was continued for 10 minutes, and the ester group and chlorine exchange product were obtained after the reaction. The target product, tetrasubstituted internal olefin compound, was separated by column chromatography with a yield of 70%; the corresponding product NMR spectrum is shown in FIG. Figure 5 and Figure 6 As shown, the data is as follows: 1 H NMR (600MHz, CDCl3) δ7.91 (dd, J=7.7, 1.0Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.74–7.71 (m, 3H), 7. 54(t,J=7.5Hz,1H),7.37(d,J=8.0Hz,2H),4.18(s,2H),3.12(s,2H),2.44(s,3H),1.50(s,6H). 13 C NMR (151MHz, CDCl3) δ166.0,144.2,140.1,136.3,134.4,131.1,130.2,129.9,129.6,128.4,126.12,126.06,124.1,63.8,53.1,41.3,25.1,21.7.

[0073] Example 5

[0074] Preparation of (Z)-Azacycloalkenyl chloride compounds

[0075] Prepare according to the reaction equation shown below:

[0076]

[0077] 1,6-enyne (50mmol) and Fe(acac)3 (0.5mmol) were added into the reactor, and D2O (75mmol) was dissolved in 10ml of dichloromethane. Benzoyl chloride (75mmol) was added dropwise in an ice-water bath at 0°C, and the mixture was heated to 80°C. After stirring for 10 minutes, the reaction was completed. The target product, a deuterium-substituted heterocyclic compound, was separated by column chromatography, i.e., the (Z)-azaheterocycloalkenyl chloride compound, with a yield of 83%.

[0078] The NMR spectra of the deuterium-substituted heterocyclic compounds are shown in Figure 2. Figure 7 and Figure 8 As shown, the data is as follows: 1 H NMR (600MHz, CDCl3) δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.33(t,J=3. 3Hz,3H),7.25–7.20(m,2H),4.04(s,2H),2.99(s,2H),2.47(s,3H),0.91(s,5H). 13 C NMR (151MHz, CDCl3) δ144.0,141.9,137.8,132.0,129.9,129.2,129.0,128.4,128.2,125.3,63.1,54.0,43.3,26.2,26.1,21.8.

[0079] Example 6

[0080]

[0081] 1,6-enyne (50mmol) and Fe(OAc)2(0.5mmol) were added into the reactor, and then D2O(75mmol) was dissolved in 10ml of dichloromethane and added into the reactor, and benzoyl chloride (75mmol) was added dropwise in a 0℃ ice-water bath, and the mixture was heated to 50℃. After stirring for 10 minutes, the reaction was completed, and the reaction temperature was raised to 100℃, and the reaction was continued for 10 minutes. After the reaction, an ester group and a chlorine exchange product were obtained, and the target product, a tetrasubstituted olefin compound, was obtained by column chromatography separation with a yield of 72%.

[0082] The corresponding NMR spectra of the products are shown in Fig. 9 and Fig.10 As shown, the data is as follows: 1 H NMR(600MHz, CDCl3)δ7.91(d,J=7.6Hz,1H),7.80(d,J=8.0Hz,1H),7.74–7.70(m,3H),7.54(t,J= 7.5Hz,1H),7.37(d,J=7.9Hz,2H),4.17(s,2H),3.11(s,2H),2.44(s,3H),1.49(d,J=10.7Hz,5H). 13 C NMR (151MHz, CDCl3) δ166.0,144.2,140.1,136.3,134.4,131.0,130.2,129.9,129 .6,128.4,126.1,126.0,124.0,63.8,63.8,53.1,41.25,41.17,25.1,25.0,21.7.

[0083] Example 7

[0084]

[0085] Under nitrogen atmosphere, the product of Example 2 (50mmol) and [Pd(allyl)Cl]2(1mmol) were added into the reactor, and then the ligand (ligand, 0.5mmol), Cs2CO3 (75mmol) was dissolved in 10ml toluene and added into the reactor, and then deuterated benzhydrol (75mmol) was added, and the mixture was heated to 90°C and stirred for 24 hours until the reaction was completed. After the reaction, a D-substituted chlorine product was obtained, and the target product was separated by column chromatography with a yield of 95%.

[0086] The corresponding NMR spectra of the products are shown in Fig.11 and 12 As shown, the data is as follows: 1 H NMR (600MHz, CDCl3) δ7.73(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),7.28–7.24(m,3H),7. 24–7.19(m,1H),7.13–7.09(m,2H),3.99(s,2H),2.99(s,2H),2.46(s,3H),1.02(s,6H). 13 C NMR (151MHz, CDCl3) δ144.8,143.7,136.9,132.7,129.8,129.0,128.0,127.9,127.0,122.5,63.1,54.3,42.3,26.1,21.7.

[0087] The same method was used to synthesize the following compounds 1-37:

[0088] 1.

[0089] The structural formula is R is a 1,6-enyne of p-methylphenyl instead of the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 67%. The NMR data for its structural confirmation are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=8.3Hz,2H),7.38(d,J=7.8Hz,2H),7.13(t,J =6.2Hz,4H),4.04(s,2H),2.99(s,2H),2.46(s,3H),2.34(s,3H),0.92(s,6H). 13C NMR (151MHz, CDCl3) δ143.9,141.7,139.0,135.0,132.2,129.9,129.1,129.0,128.2,125.5,63.1,54.0,43.3,26.2,21.7,21.4.

[0090] 2.

[0091] The structural formula is R is a 1,6-enyne of p-fluorophenyl instead of the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 68%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=8.3Hz,2H),7.38(d,J=7.9Hz,2H),7.21(dd,J=8.7,5 .3Hz,2H),7.02(t,J=8.6Hz,2H),4.04(s,2H),3.00(s,2H),2.47(s,3H),0.91(s,6H). 13 CNMR(151MHz,CDCl3)δ162.9(d,J=249.2Hz),144.0,142.7,134.0(d,J=3.5Hz),132.2,13 1.2(d,J=8.6Hz),129.9,128.2,124.3,115.5(d,J=21.9Hz),63.1,54.0,43.4,26.2,21.8. 19 F NMR(564MHz, CDCl3)δ-111.62(s,1F).

[0092] 3.

[0093] The structural formula is R is a 1,6-enyne of p-chlorophenyl instead of the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 82%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,2H),7.31(d,J=8.4 Hz,2H),7.17(d,J=8.5Hz,2H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H). 13CNMR (151MHz, CDCl3) δ144.0,142.8,136.3,135.1,132.1,130.6,129.9,128.7,128.2,124.0,63.1,54.0,43.4,26.3,21.8.

[0094] 4.

[0095] The structural formula is R is a 1,6-enyne of p-bromophenyl instead of the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 88%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.47(d,J=8.4Hz,2H),7.38(d,J=7.9 Hz,2H),7.11(d,J=8.4Hz,2H),4.03(s,2H),3.00(s,2H),2.47(s,3H),0.92(s,6H). 13 CNMR(151MHz, CDCl3)δ144.0,142.9,136.8,132.2,131.7,130.9,129.9,128.2,124.0,123.3,63.1,54.0,43.4,26.3,21.8.

[0096] 5.

[0097] The structural formula is R is 1,6-enyne of p-tert-butylphenyl instead of The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 71%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.75(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.35–7.32(m,2H) ,7.16–7.14(m,2H),4.04(s,2H),2.99(s,2H),2.47(s,3H),1.30(s,9H),0.92(s,6H). 13 C NMR (151MHz, CDCl3) δ152.2,143.9,141.7,134.9,132.2,129.9,128.8,128.2,125.6,125.2,63.2,54.0,43.3,34.8,31.4,26.2,21.8.

[0098] 6.

[0099] The structural formula is R is 1,6-enyne of p-hydroxymethylphenyl instead of The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 67%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.38(d,J=8.0Hz,2H),7.36(d,J=8.1Hz,2H) ,7.23(d,J=8.2Hz,2H),4.57(s,2H),4.05(s,2H),3.00(s,2H),2.46(s,3H),0.91(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,142.4,138.3,137.9,132.2,129.9,129.6,128.5,128.1,124.5,63.1,54.0,45.6,43.3,26.2,21.7.

[0100] 7.

[0101] The structural formula is R is a 1,6-enyne of p-biphenyl instead of the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 42%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3) δ7.76(d,J=8.0Hz,2H),7.58(dd,J=12.0,7.6Hz,4H),7.45(t,J=7.6Hz,2H),7.3 8(dd,J=14.4,7.6Hz,3H),7.31(d,J=8.0Hz,2H),4.07(s,2H),3.02(s,2H),2.48(s,3H),0.97(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,142.2,141.8,140.2,136.8,132.0,129.9,129 .7,129.0,128.2,127.9,127.2,127.0,125.0,63.1,54.1,43.4,26.3,21.8.

[0102] 8.

[0103] The structural formula is R is The 1,6-enyne in Example 2 is substituted The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 98%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ8.00(d,J=8.4Hz,2H),7.73(d,J=8.2Hz,2H),7.37(d,J=7.9Hz,2H) ,7.30(d,J=8.4Hz,2H),4.05(s,2H),3.90(s,3H),2.99(s,2H),2.45(s,3H),0.89(s,6H). 13 C NMR (151MHz, CDCl3) δ166.4,144.0,142.9,142.2,132.1,130.6,129.9,129.6,129.3,128.1,123.8,63.0,54.0,52.4,43.4,26.2,21.7.

[0104] 9.

[0105] The structural formula is R is a 1,6-enyne of p-trifluoromethylphenyl instead of the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 98%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.75(d,J=8.2Hz,2H),7.61(d,J=8.1Hz,2H),7.39(d,J=7.9 Hz,2H),7.37(d,J=8.0Hz,2H),4.06(s,2H),3.01(s,2H),2.47(s,3H),0.92(s,6H). 13 CNMR(151MHz, CDCl3)δ143.7(d,J=118.5Hz),141.4,131.9,131.0(d,J=32.8Hz),129.9(d,J=7.0Hz), 128.5,128.2,126.5,125.5(q,J=3.6Hz),123.8(q,J=273.3Hz),123.4,63.0,54.0,43.4,26.2,21.7. 19 F NMR (564MHz, CDCl3) δ-62.85 (s, CF3).

[0106] 10.

[0107] The structural formula is R is 1,6-enyne of the phenyl group of p-boronic acid pinacol ester instead of the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 91%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.76(d,J=6.0Hz,2H),7.74(d,J=6.1Hz,2H),7.37(d,J=6.7Hz,2H), 7.23(d,J=5.9Hz,2H),4.04(s,2H),2.99(s,2H),2.46(s,3H),1.33(s,12H),0.90(s,6H). 13 C NMR (151MHz, CDCl3) δ143.9,141.9,140.5,134.7,132.1,129.9,128.5,128.1,125.0,84.1,63.1,54.0,43.3,26.2,25.0,21.7.

[0108] 11.

[0109] The structural formula is 1,6-enyne in which R is m-methoxyphenyl replaces the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 71%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.74(d,J=8.2Hz,2H),7.38(d,J=7.9Hz,2H),7.25–7.22(m,1H),6.87(ddd,J=8.4,2.6,1.0Hz,1H), 6.82(dt,J=7.5,1.3Hz,1H),6.76(dd,J=2.6,1.6Hz,1H),4.04(s,2H),3.78(s,3H),3.00(s,2H),2.47(s,3H),0.94(s,6H). 13 C NMR (151MHz, CDCl3) δ159.4,144.0,141.8,139.0,132.2,129.9,129.4,128.2,125.0,121.6,114.8,114.6,63.2,55.4,54.0,43.4,26.2,21.8.

[0110] 12.

[0111] The structural formula is 1,6-enyne in which R is m-fluorophenyl replaces the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 83%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=7.8Hz,2H),7.38(d,J=7.9Hz,2H),7.30(q,J=7.6Hz,1H),7.0 2(t,J=6.2Hz,2H),6.94(d,J=9.2Hz,1H),4.04(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H). 13 C NMR(151MHz,cdcl3)δ162.2(d,J=247.9Hz),144.0,142.7,139.6(d,J=8.0Hz),132.0,130.0(d,J=8.6Hz),129.9, 128.1, 125.1 (d, J = 3.0Hz), 123.6 (d, J = 2.3Hz)., 116.4, 116.2 (dd, J = 35.2, 21.4Hz), 63.0, 54.0, 43.3, 26.1, 21.7.

[0112] 13.

[0113] The structural formula is 1,6-enyne in which R is m-chlorophenyl replaces the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 91%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.33–7.30(m,1H),7.27(t,J=7.7Hz,2 H),7.22(t,J=1.8Hz,1H),7.12(dt,J=7.5,1.4Hz,1H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,143.0,139.4,134.2,132.0,129.9,129.7,129.3,129.2,128.1,127.4,123.6,63.0,54.0,43.4,26.2,21.7.

[0114] 14.

[0115] The structural formula is 1,6-enyne in which R is m-bromophenyl replaces the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 76%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.73(d,J=7.9Hz,2H),7.47(d,J=7.9Hz,1H),7.38(d,J=8.4Hz,3H),7.2 1(t,J=7.8Hz,1H),7.17(d,J=7.7Hz,1H),4.03(s,2H),3.00(s,2H),2.46(s,3H),0.92(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,143.0,139.6,132.2,132.1,131.9,130.0,129.9,128.1,127.9,123.4,122.2,63.0,54.0,43.4,26.2,21.8.

[0116] 15.

[0117] The structural formula is R is a 1,6-enyne of m-trifluoromethylphenyl instead of the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 66%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.74(d,J=8.2Hz,2H),7.60(d,J=7.5Hz,1H),7.51–7.46(m,2H),7.43 (d,J=7.9Hz,1H),7.38(d,J=7.9Hz,2H),4.06(s,2H),3.01(s,2H),2.46(s,3H),0.90(s,6H). 13 C NMR (151MHz, CDCl3) δ143.8 (d, J = 85.0Hz), 138.6, 132.6, 132.0, 130.9 (q, J = 32.8Hz), 130.0, 129.1, 128.2 ,126.2(q,J=3.7Hz),125.8(q,J=3.7Hz),123.7(q,J=273.3Hz),122.8,63.04,54.06,43.37,26.24,21.73. 19 F NMR(564MHz, CDCl3)δ-58.67(s,3F).

[0118] 16.

[0119] The structural formula is R is The 1,6-enyne in Example 2 is substituted The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 79%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ8.03–7.99(m,1H),7.92(d,J=1.2Hz,1H),7.74(d,J=8.2Hz,2H),7.44–7.4 1(m,2H),7.38(d,J=7.9Hz,2H),4.05(s,2H),3.90(s,3H),3.00(s,2H),2.47(s,3H),0.90(s,6H). 13 C NMR (151MHz, CDCl3) δ166.4,144.0,142.9,138.1,133.5,132.0,130.4,130.1,129.9,128.6,128.1,124.0,63.1,54.0,52.4,43.4,26.3,21.7.

[0120] 17.

[0121] The structural formula is 1,6-enyne in which R is o-fluorophenyl replaces the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 79%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=7.8Hz,2H),7.38(d,J=8.0Hz,2H),7.35(t,J=6.9Hz,1H),7.23–7.19(m,1H),7.13(t,J=7.5Hz,1H),7.08–7.0 4(m,1H),4.18(d,J=15.8Hz,1H),3.95(d,J=15.6Hz,1H),3.13(d,J=8.9Hz,1H),2.90(d,J=8.9Hz,1H),2.47(s,3H),1.03(s,3H),0.79(s,3H). 13 C NMR (151MHz, CDCl3) δ159.6 (d, J = 249.3Hz), 144.7, 144.4 (d, J = 94.7Hz), 132.0, 131.5 (d, J = 2.3Hz), 131.4 (d, J =8.2Hz), 130.0, 128.1, 125.4 (d, J = 16.2Hz), 124.1, 118.7, 116.1 (d, J = 21.4Hz), 53.9, 43.4, 26.9, 23.9, 21.7.

[0122] 18.

[0123] The structural formula is R is α-naphthyl 1,6-enyne instead of the The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 40%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.85(t,J=8.2Hz,2H),7.83–7.80(m,1H),7.79(d,J=7 .9Hz,2H),7.52–7.47(m,2H),7.44(d,J=7.4Hz,1H),7.41(d,J=8.2Hz,2H),7 .37(d,J=6.9Hz,1H),4.30(d,J=15.5Hz,1H),4.16(d,J=15.6Hz,1H),3.14(d ,J=9.0Hz,1H),2.93(d,J=9.0Hz,1H),2.49(s,3H),1.06(s,3H),0.52(s,3H). 13 C NMR (151MHz, CDCl3) δ144.0,143.8,134.7,133.7,132.5,131.2,130.0,129.8,128.5, 128.2,127.9,126.8,126.4,125.6,125.0,123.8,63.0,53.9,43.6,27.2,24.2,21.8.

[0124] 19.

[0125] The structural formula is R is β-naphthyl 1,6-enyne instead of the The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 50%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.82(dd,J=11.5,8.8Hz,3H),7.77(d,J=7.9Hz,2H),7.72(d,J=1.6Hz,1H),7.51(tt,J=5.8, 4.6Hz,2H),7.39(d,J=7.9Hz,2H),7.32(dd,J=8.5,1.7Hz,1H),4.12(s,2H),3.02(s,2H),2.48(s,3H),0.94(s,6H). 13C NMR (151MHz, CDCl3) δ144.0,142.4,135.2,133.2,132.7,132.2,129.9,128.6,128. 33,128.27,128.2,127.8,127.1,126.8,126.6,125.4,63.2,54.1,43.4,26.3,21.8.

[0126] 20.

[0127] The structural formula is R is 2-thienyl 1,6-enyne instead of the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 43%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.73(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.28(td,J=2.9,1.4Hz,1H),7.22( dt,J=2.9,1.1Hz,1H),6.96(dt,J=5.0,1.2Hz,1H),4.01(s,2H),2.99(s,2H),2.46(s,3H),0.96(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,143.5,137.5,131.9,129.9,128.3,128.2,125.9,125.5,120.1,63.1,54.1,43.4,26.0,21.8.

[0128] twenty one,

[0129] The structural formula is The 1,6-enyne in Example 2 is substituted The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 66%. The corresponding product NMR data are as follows: 1 H NMR(600MHz, CDCl3)δ7.71(d,J=8.2Hz,2H),7.36(d,J=7.9Hz,2H),7.19–7.13(m,3H),7.12–7.09(m,1H),7.05(dd,J=7.8,1.9Hz,2H),7 .01(t,J=7.8Hz,2H),6.79(d,J=7.0Hz,2H),4.30–4.23(m,2H),3.47(d,J=9.3Hz,1H),3.24(d,J=9.3Hz,1H),2.47(s,3H),1.28(s,3H).13 CNMR(151MHz,CDCl3)δ144.9,144.0,142.4,137.2,132.3,129.9,128.8,128 .5,128.3,128.1,127.8,127.2,126.8,126.5,65.2,54.8,50.3,23.9,21.8.

[0130] twenty two,

[0131] The structural formula is The 1,6-enyne in which R is -Et replaces the one in Example 2 The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 41%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ7.70(d,J=8.3Hz,2H),7.35(d,J=7.8Hz,2H),3.83(s,2H),2.98 (s,2H),2.44(s,3H),2.38(qt,J=7.3,1.3Hz,2H),1.24(s,6H),1.08(t,J=7.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ143.9,138.8,131.8,130.7,129.8,128.2,63.4,54.1,42.5,28.7,26.2,21.7,12.8.

[0132] twenty three,

[0133] The structural formula is The 1,6-enyne in which R is -nBu replaces the The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 60%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ7.70(d,J=7.9Hz,2H),7.35(d,J=7.9Hz,2H),3.83(s,2H),2.98(s,2H),2.45(s ,3H),2.34(t,J=7.9Hz,2H),1.53–1.46(m,2H),1.33–1.27(m,2H),1.24(s,6H),0.90(t,J=7.3Hz,3H). 13C NMR (151MHz, CDCl3) δ144.0,139.0,131.5,129.8,129.6,128.3,63.4,54.2,42.5,35.1,30.3,26.3,22.4,21.7,14.1.

[0134] twenty four,

[0135] The structural formula is The 1,6-enyne in which R is -H replaces the one in Example 2 The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 64%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.67(d,J=8.0Hz,2H),7.34(d,J=7.9Hz,2H),5.64(s,1H),3.59(s,2H),2.82(s,2H),2.44(s,3H),1.08(s,6H). 13 C NMR (151MHz, CDCl3) δ144.0,133.3,133.2,130.0,127.7,124.8,54.3,49.2,35.5,26.6,21.7.

[0136] 25.

[0137] The structural formula is The 1,7-enyne in Example 3 is substituted The (Z)-azacycloalkenyl chloride compound was obtained with a yield of 71%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.78(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),7.30(dd,J=4.7,1.8Hz,3H),7.1 7–7.14(m,2H),4.23(s,2H),3.26(t,J=6.1Hz,2H),2.47(s,3H),1.47(t,J=6.1Hz,2H),0.74(s,6H). 13 C NMR (151MHz, CDCl3) δ143.6,140.7,136.8,134.4,129.8,129.0,128.8,128.5,128.2,127.8,46.9,42.3,39.6,36.3,29.0,21.7.

[0138] 26.

[0139] The structural formula is The enyne in Example 3 is replaced by The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 90%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.76–7.72(m,2H),7.39–7.35(m,2H),7.31–7.27(m,5H),3.45–3.42(m,2 H),3.40(d,J=7.2Hz,2H),2.71(t,J=7.3Hz,2H),2.41(s,3H),2.11–2.07(m,2H),1.56(s,6H). 13 C NMR (151MHz, CDCl3) δ143.6,136.6,131.7,129.9,128.4,128.1,127.3,123.3,86.5,82.6,68.8,47.9,45.8,44.5,32.7,21.6,20.7.

[0140] 27.

[0141] The structural formula is R is The 1,6-enyne in Example 2 is substituted The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 32%. The corresponding product NMR data are as follows: 1 HNMR(600MHz, CDCl3)δ8.20(dd,J=7.9,1.7Hz,1H),7.76(d,J=8.4Hz,2H),7.68–7.65(m,1H),7.41–7.38(m,1H),7.30 –7.27(m,2H),7.19–7.17(m,1H),7.08–7.04(m,4H),4.67(s,2H),3.58(s,2H),2.36(s,3H),2.30(s,3H),1.72(s,6H). 13 C NMR (151MHz, CDCl3) δ169.7,162.6,151.2,150.4,143.8,136.1,134.8,132.8,132.1,129.6 ,127.9,126.2,124.1,122.2,121.6,120.1,85.1,82.1,69.9,57.6,39.6,30.9,21.4,21.0.

[0142] 28.

[0143] The structural formula is R is The 1,6-enyne in Example 2 is substituted The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 63%. The corresponding product NMR data are as follows: 1 HNMR (600MHz, CDCl3) δ10.39(s,1H),7.75(d,J=8.2Hz,2H),7.55(ddd,J=8.6,7.2,1.7Hz,1H),7.39(d,J=8.0Hz,2H),7.32(d,J=8.6Hz,2H) ,7.21(d,J=8.6Hz,2H),7.04(dd,J=8.4,1.1Hz,1H),6.97(ddd,J=8.2,7.2,1.2Hz,1H),4.06(s,2H),3.02(s,2H),2.47(s,3H),0.96(s,6H). 13 C NMR (151MHz, CDCl3) δ168.6,162.4,150.4,144.0,142.9,136.8,136.0,132.2,130.7, 130.4,129.9,128.2,124.2,121.8,119.7,118.0,111.7,63.1,54.1,43.4,26.3,21.8.

[0144] 29.

[0145] The structural formula is R is The 1,6-enyne in Example 2 is substituted The (Z)-azaheterocycloalkenyl chloride compound was obtained with a yield of 77%. The corresponding product NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ8.03(d,J=8.1Hz,2H),7.76(d,J=8.0Hz,2H),7.39(d,J=8.1Hz,2H),7.33 (d,J=8.1Hz,2H),4.95(td,J=10.9,4.4Hz,1H),4.08(s,2H),3.03(s,2H),2.46(s,3H),2.11(d, J=12.3Hz,1H),1.96(td,J=6.9,2.7Hz,1H),1.79–1.69(m,2H),1.56(tt,J=8.0,3.3Hz,2H),1.2 8(d,J=8.3Hz,1H),1.12(t,J=11.7Hz,2H),0.93(dd,J=7.7,5.8Hz,12H),0.80(d,J=7.0Hz,3H).13 C NMR (151MHz, CDCl3) δ165.2,143.8,142.7,141.9,131.9,131.1,129.8,129.5,129.2,128.0,123. 8,75.1,62.9,53.9,47.1,43.2,40.9,34.2,31.4,26.4,26.1,26.0,23.5,22.0,21.6,20.8,16.4.

[0146] 30.

[0147] The structural formula is R is a 1,6-enyne of p-fluorophenyl instead of the one in Example 5 The deuterium-substituted heterocyclic compound was prepared with a yield of 77%. The NMR data for its structural confirmation are as follows: 1 HNMR (600MHz, CDCl3) δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.21(dd,J=8.5,5.4Hz ,2H),7.02(t,J=8.6Hz,2H),4.03(s,2H),2.99(s,2H),2.46(s,3H),0.90(d,J=10.4Hz,5H). 13 C NMR(151MHz,cdcl3)δ162.8(d,J=249.2Hz),142.7,133.9(d,J=3.5Hz),132.0,131.2(d,J =8.5Hz),129.9,128.2,124.2,115.5(d,J=21.8Hz),63.0,54.0,43.2,26.20,26.18,21.7. 19 F NMR(564MHz, CDCl3)δ-111.57(s,1F).

[0148] 31.

[0149] The structural formula is R is a 1,6-enyne of p-hydroxymethylphenyl instead of the The deuterium-substituted heterocyclic compound was prepared with a yield of 70%. The corresponding product NMR data are as follows: 1H NMR (600MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.37(dd,J=13.2,8.0Hz,4H),7.23(d,J=8 .2Hz,2H),4.57(s,2H),4.04(s,2H),2.99(s,2H),2.46(s,3H),0.90(d,J=10.6Hz,5H). 13 C NMR (151MHz, CDCl3) δ144.0,142.4,138.3,137.9,132.0,129.9,129.6,128.5,128.1,124.5,63.0,54.0,45.6,43.3,26.2,26.2,21.7.

[0150] 32.

[0151] The structural formula is R is a 1,6-enyne of p-trifluoromethylphenyl instead of the one in Example 5 The deuterium-substituted heterocyclic compound was prepared with a yield of 89%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.74(d,J=8.2Hz,2H),7.61(d,J=7.3Hz,2H),7.37(dd,J=1 3.2,7.9Hz,4H),4.05(s,2H),3.00(s,2H),2.46(s,3H),0.90(d,J=10.0Hz,5H). 13 C NMR(151MHz, CDCl3)δ143.7(d,J=118.5Hz),141.4,131.9,131.0(d,J=32.8Hz),129.9(d,J=7.0Hz),128.5,128 .2,126.5,125.5(q,J=3.6Hz),123.8(q,J=273.3Hz),123.4,122.9,110.1,63.0,54.0,43.3,26.3,26.2,21.8. 19 F NMR (564MHz, CDCl3) δ-62.80 (s, 1F).

[0152] 33.

[0153] The structural formula is R is 1,6-enyne of the phenyl group of p-boronic acid pinacol ester instead of the one in Example 5 The deuterium-substituted heterocyclic compound was prepared with a yield of 65%. The corresponding product NMR data are as follows: 1HNMR(600MHz, CDCl3) δ7.75(dd,J=15.6,7.8Hz,4H),7.38(d,J=7.9Hz,2H),7.23(d,J=7 .7Hz,2H),4.04(s,2H),2.98(s,2H),2.46(s,3H),1.33(s,12H),0.89(d,J=10.6Hz,5H). 13 C NMR (151MHz, CDCl3) δ144.0,141.9,140.5,135.0,134.7,132.0,129.9,12 8.5,128.2,125.0,84.2,63.1,54.0,43.3,43.3,26.20,26.18,25.0,21.8.

[0154] 34.

[0155] The structural formula is 1,6-enyne in which R is m-methoxyphenyl replaces the one in Example 5 The deuterium-substituted heterocyclic compound was prepared with a yield of 72%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),7.24(t,J=8.0Hz,1H),6.87(dd,J=8.4,2.5Hz, 1H), 6.83–6.80 (m, 1H), 6.76 (s, 1H), 4.03 (s, 2H), 3.78 (s, 3H), 2.99 (s, 2H), 2.46 (s, 3H), 0.93 (d, J = 10.5Hz, 5H). 13 C NMR (151MHz, CDCl3) δ159.3,143.9,141.8,139.0,132.1,129.9,129.4,128 .1,125.0,121.6,114.7,114.6,63.1,55.4,54.0,43.3,26.12,26.09,21.7.

[0156] 35.

[0157] The structural formula is R is The 1,6-enyne in Example 5 is substituted The deuterium-substituted heterocyclic compound was prepared with a yield of 74%. The corresponding product NMR data are as follows: 1H NMR(600MHz, CDCl3)δ8.01(td,J=4.7,1.7Hz,1H),7.91(s,1H),7.73(d,J=8.1Hz,2H),7.44–7.41(m,2 H),7.38(d,J=7.9Hz,2H),4.05(s,2H),3.90(s,3H),2.99(s,2H),2.46(s,3H),0.89(d,J=10.4Hz,5H). 13 C NMR (151MHz, CDCl3) δ166.4,144.3,144.0,142.9,138.1,133.5,131.9,130.4 ,130.1,129.9,128.6,128.1,124.0,63.0,54.0,52.4,43.2,26.3,26.2,21.7.

[0158] 36.

[0159] The structural formula is The 1,6-enyne in Example 5 is substituted The deuterium-substituted heterocyclic compound was prepared with a yield of 65%. The corresponding product NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ7.71(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),7.16(d,J=7.4Hz,3H),7.11(t,J=7.6Hz,1H),7.07–7.04(m,2H),7. 02(t,J=7.6Hz,2H),6.80(d,J=7.7Hz,2H),4.31–4.23(m,2H),3.48(d,J=9.3Hz,1H),3.24(d,J=9.3Hz,1H),2.47(s,3H),1.27(s,2H). 13 CNMR(151MHz,CDCl3)δ144.9,144.0,142.3,137.1,132.1,129.9,128.7,128 .5,128.3,128.1,127.8,127.2,126.8,126.4,65.2,54.8,50.1,23.8,21.7.

[0160] 37.

[0161] The structural formula is The enyne in Example 5 is replaced by The deuterium-substituted heterocyclic compound was prepared with a yield of 69%. The corresponding product NMR data are as follows: 1H NMR (600MHz, CDCl3) δ7.78(d,J=8.3Hz,2H),7.37(d,J=8.0Hz,2H),7.30(dd,J=5.0,1.9Hz,3H),7.17–7 .14(m,2H),4.23(s,2H),3.27–3.24(m,2H),2.47(s,3H),1.46(t,J=6.1Hz,2H),0.73(d,J=12.7Hz,5H). 13 C NMR (151MHz, CDCl3) δ143.6,140.7,136.7,134.3,129.8,128.9,128.8,128.5,128.2,127.8,46.8,42.3,39.5,36.3,36.2,29.0,28.9,21.7.

[0162] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a (Z)-nitrogen heterocyclic alkenyl chloride compound, characterized in that: The following steps are involved: The ene acetylene compound is mixed with a metal iron salt catalyst, and then water or a dichloromethane solution of heavy water and Cl are added. - Reagent, heating reaction, to obtain the (Z)-azaheterocycloalkenyl chloride compound; the structural formula of the (Z)-azaheterocycloalkenyl chloride compound is Any one of; the structural formula of the enyne compound is Among them, R 1 is one of a hydrogen atom, an alkyl substituent and an aryl substituent; R 2 is one of an alkyl substituent and an aryl substituent; n1 is an integer of 1-5, n2 is an integer of 1-5; the Cl - The reagent is at least one of acetyl chloride, benzoyl chloride, and trimethylsilyl chloride TMSCl; the aromatic substituent is phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-hydroxymethylphenyl, p-methylphenyl, p-tert-butylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boric acid pinacol ester phenyl, p-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-methoxyphenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl, The metal iron salt catalyst is a mixture of one or more of Fe(acac)2, Fe(OAc)2, FeCl2, FeCl3, Fe2(SO4)3, and Fe(acac)3.

2. The method for preparing the (Z)-nitrogen heterocyclic alkenyl chloride compound according to claim 1, characterized in that: R 1 and R 2 In the above, the alkyl substituent is a C1-C10 alkyl group.

3. The method for preparing the (Z)-nitrogen heterocyclic alkenyl chloride compound according to claim 1, characterized in that: The R 1 is phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-tert-butylphenyl, p-hydroxymethylphenyl, p-biphenyl, p-trifluoromethylphenyl, p-boronic acid pinacol ester phenyl, m-methoxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-trifluoromethylphenyl, o-fluorophenyl, α-naphthyl, β-naphthyl, 2-thienyl, ethyl, n-butyl, hydrogen, One of the 2 It is one of methyl and phenyl.

4. The method for preparing the (Z)-azacycloalkenyl chloride compound according to any one of claims 1 to 3, characterized in that: The enyne compound, Cl - The molar ratio of the reagent to water or heavy water is 1:1-5:1-5; the molar ratio of the metal iron salt catalyst to the ene-yne ​​compound is 0.5-30:100; the reaction temperature is 20°C-100°C, and the reaction time is 0.1-1 hour.

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