A method for the nitrous oxide mediated preparation of five-membered azo compounds

Abstract

The application discloses a method for preparing a five-membered azo compound mediated by laughing gas, and comprises the following steps: S1, reacting gem-boronate compounds shown in formula I with laughing gas in the presence of a solvent and a base reagent to obtain a diazo compound; S2, adding olefin compounds shown in formula II to the reaction system containing the diazo compound to continue the reaction to obtain five-membered azo compounds shown in formula III. The preparation method uses laughing gas as a nitrogen source, and cheap and easily obtained gem-boronate and olefin as reaction raw materials, so that known and novel five-membered azo compounds can be prepared by one-pot method. The preparation method is simple, the reaction condition is mild, and the reaction yield is high, and the method is suitable for industrialized production of the five-membered azo compounds. In addition, the five-membered azo compounds prepared by the application can be used for further conversion to prepare cyclopropane compounds and 1,3-diamine compounds, and have important application value in the fields of biological medicines, pesticides and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing pentazocine compounds mediated by nitrous oxide. Background Technology

[0002] Azo compounds (-N=N-) are a class of valuable organic functional molecules. Due to their unique photoisomerism and electronic effects, they show broad application prospects in various fields such as photoresponsive materials, functional polymers and smart materials, chemical sensing and detection, biomedicine, and organic synthesis intermediates. In particular, five-membered azo compounds (e.g., (Adv. Synth. Catal. 2024, 366, 114–120). Compared to ordinary chain azo compounds, their cyclic structure endows the molecules with unique conformational rigidity and excellent conformational stability, and exhibits superior photophysical properties, thus possessing unique value in new material development and drug molecule modification. However, current research on synthetic methodologies for five-membered azo compounds remains relatively limited. Their synthetic strategies are highly dependent on the specific skeletal structure and substituent types of the target molecule, which severely restricts the widespread development and application exploration of this class of compounds.

[0003] Currently, the existing technologies for synthesizing five-membered azo compounds mainly include the following approaches:

[0004] (1) Oxidative coupling method: This method is a classic route for synthesizing symmetrical azo compounds, but its applicability is relatively narrow, usually limited to substrates with specific structures. More importantly, this method generally requires the use of highly toxic heavy metals such as lead tetraacetate (Pb(OAc)4) as oxidants, which poses safety hazards in the reaction process and does not conform to the development concept of modern green chemistry.

[0005] (2) 1,3-Dipole Cycloaddition: 1,3-Dipole cycloaddition is an efficient tool for constructing five-membered heterocyclic skeletons. However, when applied to the synthesis of five-membered azo compounds, this method usually faces the problem of harsh reaction conditions, often requiring high temperature or high pressure, or relying on noble metal catalysts (such as gold, copper, silver, etc.). This not only increases production costs, but the residual problem of metal catalysts also limits its application in fields with high purity requirements, such as biomedicine.

[0006] (3) Electrochemical oxidation method: In recent years, the electrochemical oxidation method has attracted attention as a green synthesis method, but there are still many technical bottlenecks when it is used to synthesize five-membered azo compounds. First, the cost of electrode materials (such as NiO(OH)) is high, and some reaction systems require special electrolysis devices, which is not conducive to industrial promotion. Second, the reaction efficiency is affected by multiple factors such as current density, electrolyte pH value and substrate concentration, and the parameter optimization process is complicated. In addition, due to the adsorption of organic substrates or intermediates on the electrode surface, high concentrations of substrates can easily lead to electrode passivation, which seriously affects the reproducibility of the reaction and the current efficiency.

[0007] Given the shortcomings of existing methods for synthesizing five-membered azo compounds, such as high toxicity, harsh conditions, high cost, or complex processes, there is an urgent need for a green, environmentally friendly, simple, and efficient method for synthesizing five-membered azo compounds to meet diverse synthesis needs and industrial production requirements. Summary of the Invention

[0008] To address the shortcomings of existing methods for synthesizing five-membered azo compounds, such as high toxicity, demanding conditions, high costs, or complex processes, this invention provides a nitrous oxide-mediated method for preparing five-membered azo compounds. Using nitrous oxide as the nitrogen source and readily available, inexpensive geminolates and alkenes as reactants, this method can prepare known and a series of novel five-membered azo compounds in a one-pot process. This method is simple, has mild reaction conditions, and achieves high yields, making it suitable for the industrial production of five-membered azo compounds. Furthermore, the five-membered azo compounds prepared by this invention can be further converted into cyclopropane compounds and 1,3-diamine compounds, possessing significant application value in the fields of biomedicine and pesticides.

[0009] Specifically, the following technical solutions are provided:

[0010] This invention provides a method for preparing pentazocine compounds mediated by nitrous oxide, comprising the following steps: under a protective atmosphere,

[0011] S1. The geminiboronic acid ester compound shown in Formula I is reacted with nitrous oxide in the presence of a solvent and an alkaline reagent to obtain an intermediate product;

[0012] S2. Add the olefin compound shown in Formula II to the above reaction system containing the intermediate product and continue the reaction to obtain the five-membered azo compound shown in Formula III.

[0013] The structures of equations I, II, and III above are shown below:

[0014] ,

[0015] Wherein, R is a substituted or unsubstituted alkyl group, and the substituent of the substituted alkyl group is selected from one or more of the following groups: phenyl, halogenated and / or alkyl-substituted phenyl, benzyloxy-substituted phenyl, heteroaryl, halogenated and / or alkyl-substituted heteroaryl, heterocyclophenyl, halogenated and / or alkyl-substituted heterocyclophenyl, naphthyl, halogenated or alkyl-substituted naphthyl, halophenoxy, styryl.

[0016] R1 is selected from alkyl or haloalkyl;

[0017] R2 is selected from aryl, NPh2C(O)-, and R'OC(O)-;

[0018] R' is selected from alkyl, aryl, and aryl-substituted alkyl.

[0019] In this invention, the term "alkyl" refers to a fully saturated straight-chain or branched alkane group, including C 1-10 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, etc.

[0020] In this invention, the term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0021] In this invention, the term "heteroaryl" refers to an aryl group containing one or more heteroatoms, including but not limited to O, S, N, etc., such as furanyl, thiophene, pyrrole, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.

[0022] In this invention, the term "heterocyclic phenyl" refers to a fused ring formed by a heterocycle containing one or more heteroatoms and a phenyl group. The heteroatoms include, but are not limited to, O, S, N, etc., and the heterocyclic phenyl includes, but is not limited to, [other types of heterocycles]. .

[0023] In this invention, the term "aryl" refers to a monovalent group formed by removing a hydrogen atom from an aromatic ring molecule, including but not limited to phenyl, naphthyl, etc.

[0024] Further, in step S1, the geminoboronate compound represented by Formula I is first dissolved in a solvent, and an alkaline reagent is added dropwise to carry out a primary reaction. Then, nitrous oxide is introduced to carry out a secondary reaction to obtain an intermediate product. Preferably, the temperature of the primary reaction is 0-5 °C, and the reaction time is 0.5-1 h; the temperature of the secondary reaction is 10-40 °C, and the reaction time is 1-4 h.

[0025] Furthermore, in step S1, the molar ratio of the geminolate ester compound to nitrous oxide is 1:(1-3), for example, 1:1, 1:2, 1:3, etc., and the nitrous oxide content in the reaction vessel is less than 1 atm. If the pressure generated by the nitrous oxide in the reaction vessel is greater than 1 atm, it will cause the intermediate diazo compound to be oxidized, and the yield of the product obtained by further cycloaddition with the olefin will decrease.

[0026] Further, in step S1, the solvent is selected from one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, dimethyl ether, and benzene, more preferably tetrahydrofuran.

[0027] Further, in step S1, the alkaline reagent is lithium diisopropylamino and / or lithium tetramethylpiperidine, more preferably lithium diisopropylamino.

[0028] Further, in step S2, the molar ratio of the olefin compound represented by Formula II to the geminoboronate compound represented by Formula I is 1:(1.5-2.5), for example 1:2.

[0029] Furthermore, in step S2, the reaction temperature is 10-40 °C and the reaction time is 2-4 h.

[0030] Furthermore, since the above reaction involves the presence of carbanion intermediates, the entire preparation process must be carried out under a protective atmosphere, which includes, but is not limited to, nitrogen.

[0031] Furthermore, R is selected from C 1-6 Alkyl, phenyl substituted C 1-6 Alkyl, halophenyl substituted C 1-6 Alkyl, dihydrofuranophenyl-substituted C 1-6 Alkyl, naphthyl substituted C 1-6 Alkyl, benzyloxyphenyl substituted C 1-6 Alkyl, thiazolyl substituted C 1-6 Alkyl, alkyl-substituted thiazolyl-substituted C 1-6 Alkyl, thiophene-substituted C 1-6 Alkyl, halophenoxy substituted C 1-6 Alkyl, styrene-substituted C 1-6 One of the alkyl groups, such as methyl, ethyl, propyl, F-phenylethyl, C1-phenylethyl, dihydrofuranophenyl ( Ethyl, naphthylethyl, benzyloxyphenylethyl, methyl-substituted thiazolylethyl, F-substituted phenoxypropyl, styrylmethyl, etc.

[0032] Furthermore, R1 is selected from C 1-6 Alkyl, Halogenated C 1-6One of the alkyl groups, such as methyl, ethyl, propyl, butyl, trifluoromethyl, etc.

[0033] Furthermore, R2 is selected from biphenyl, NPh2C(O)-, , One of them.

[0034] Furthermore, the geminoboronate compounds represented by Formula I are selected from one of the compounds shown in the following structures:

[0035] .

[0036] Furthermore, the olefinic compound represented by Formula II is selected from one of the compounds shown in the following structures:

[0037] .

[0038] Furthermore, the five-membered azo compounds include compounds with the following structures:

[0039] , , , , , , , , , , , , , .

[0040] This invention also provides the application of the five-membered azo compounds prepared by the above method in the preparation of cyclopropane compounds or 1,3-diamine compounds.

[0041] Furthermore, under a protective atmosphere, the five-membered azo compound is subjected to a photo-irradiation reaction in the presence of a solvent and a photosensitizer to obtain the cyclopropane compound shown in Formula IV;

[0042] .

[0043] Furthermore, the solvent includes, but is not limited to, tetrahydrofuran, and the photosensitizer includes, but is not limited to, 9-thioxanone.

[0044] Furthermore, the light wavelength of the photoreaction is 390-420 nm, and the reaction time is 8-16 h, for example, 12 h under 420 nm light conditions.

[0045] Furthermore, under a protective atmosphere, the five-membered azo compound is reacted in the presence of a solvent and a reducing agent to obtain the 1,3-diamine compound shown in Formula V;

[0046] .

[0047] Furthermore, the solvent includes, but is not limited to, tetrahydrofuran, and the reducing agent includes, but is not limited to, lithium aluminum hydride and titanium tetrachloride. In some preferred embodiments, the reducing agent is a mixed reducing agent obtained by mixing lithium aluminum hydride and titanium tetrachloride in a molar ratio of 10:1.

[0048] Furthermore, the reaction is carried out at a temperature of 10-40 °C for a time of 18-30 h, for example, 24 h.

[0049] The beneficial effects of this invention are:

[0050] This invention provides a method for preparing pentazocine compounds using nitrous oxide as a nitrogen source, with inexpensive and readily available geminoboronic esters and alkenes as reactants. Known and a series of novel pentazocine compounds can be prepared in a one-pot process, providing a green and simple method for the preparation of pentazocine compounds. Moreover, the reaction conditions of this method are mild, the yield is high (NMR yield can be up to 99%), and it can be scaled up for industrial production of pentazocine compounds.

[0051] The five-membered azo compounds prepared by this invention can be used for further conversion to prepare cyclopropane compounds and 1,3-diamine compounds, which have important application value in the fields of biomedicine and pesticides. Attached Figure Description

[0052] Figure 1 The five-membered azo compound III-1 prepared in Example 1 1 H NMR spectrum;

[0053] Figure 2 The five-membered azo compound III-2 prepared in Example 2 1 H NMR spectrum;

[0054] Figure 3 The five-membered azo compound III-3 prepared in Example 3 1 H NMR spectrum. Detailed Implementation

[0055] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The terms “comprising” or “including” used in this invention may also be replaced with the closed form “is” or “consisting of”.

[0057] In this invention, unless otherwise specified, all equipment and raw materials are available from the market or commonly used in the industry. Unless otherwise specified, the methods in the following embodiments are conventional methods in the art.

[0058] In the following examples, nuclear magnetic resonance (NMR) 1 H, 13 C{ 1 H}、 19 F{ 1 The NMR data were determined on an AVANCEIII HD-400 MHz liquid superconducting NMR spectrometer. Chemical shifts were calibrated using solvent residual peaks or external standards. Chemical shifts (δ) are expressed in ppm, and coupling constants are expressed in Hz. NMR peak shapes are represented as follows: s for singlet, d for doublet, t for triplet, m for multiplet, and brs for broad peak.

[0059] Example 1: This example relates to the preparation of the five-membered azo compound III-1, as detailed below:

[0060]

[0061] Under a nitrogen atmosphere, the compound was added to a 10 mL Shrek tube. The reaction mixture was prepared with 0.2 mmol of diisopropylaminolithium and 2.0 mL of tetrahydrofuran solvent. The reaction system was then cooled to 0 °C, and 0.2 mmol of diisopropylaminolithium was added. The reaction was then carried out at 0 °C for 0.5 h. The reaction system was then moved to room temperature, the glass stopper was replaced with a rubber stopper, and an equivalent amount of nitrous oxide (N2O) was introduced into the reaction system through a syringe. The reaction was continued at room temperature for 2 h, and then the compound was added under a nitrogen atmosphere. (0.1 mmol), continue the reaction for 4 hours. After the reaction is complete, the target product, the five-membered azo compound III-1, is obtained by column chromatography with a yield of 90% and dr 3.3:1.

[0062] 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.5 Hz, 2H), 7.57 (q, J = 4.0Hz, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.40 - 7.35 (m, 1H), 7.26 - 7.20 (m, 2H),7.00 (t, J = 8.7 Hz, 2H), 4.40 (p, J = 7.8 Hz, 1H), 2.99 (ddp, J = 21.1,14.1, 7.3 Hz, 2H), 2.50 - 2.37 (m, 1H), 2.39 (dd, J = 13.1, 8.1 Hz, 1H), 2.05(ddt, J = 13.9, 8.8, 7.1 Hz, 1H), 1.81 (dd, J = 13.1, 8.6 Hz, 1H).

[0063] 13 C NMR (101 MHz, CDCl3): δ 161.50 (d, J = 243.9 Hz), 142.07, 140.01,136.37 (d, J = 2.6 Hz), 133.23, 129.86, 128.88, 127.79, 127.52, 127.34,127.11, 124.43 (q, J = 282.1 Hz), 115.39 (d, J = 20.8 Hz), 97.75 (q, J = 26.6Hz), 89.15, 34.86, 32.35, 31.61.

[0064] 19 F NMR (376 MHz, CDCl3): δ -73.71 (s), -116.91 (m).

[0065] In addition, this example investigated the effect of different solvents on the yield, with all other conditions being the same. The following yields are NMR yields tested before purification (some product is lost during the purification process), as shown in Table 1 below:

[0066] Table 1. Yields of target products prepared with different solvents

[0067]

[0068] As shown in Table 1, the yields of the target products prepared using tetrahydrofuran, 2-methyl-tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, dimethyl ether, and benzene as solvents are all no less than 80%. Among them, the yield of the target product prepared using tetrahydrofuran as solvent can reach as high as 99%, while the target product cannot be obtained using cyclopentyl methyl ether as solvent.

[0069] This example investigated the effect of different base reagents on the yield. All other conditions were kept consistent. The following yields are the NMR yields tested before purification, as shown in Table 2 below:

[0070] Table 2. Yields of target products prepared with different base reagents

[0071]

[0072] As shown in Table 2, using lithium diisopropylamino and lithium tetramethylpiperidine as base reagents can not only prepare the target product, but also achieve a product yield of no less than 80%. However, other strong bases such as lithium n-butyl, lithium bistrimethylsilylamino, lithium methyl, lithium tert-butoxide, and lithium methoxide cannot obtain the target product.

[0073] This example investigated the effect of different nitrous oxide injection rates on the yield. All other conditions were kept consistent. The following yields are the NMR yields tested before purification, as shown in Table 3 below:

[0074] Table 3. Yields of target products prepared with different nitrous oxide injection rates

[0075]

[0076] As shown in Table 3, excessive nitrous oxide content in the reaction vessel can actually lead to a decrease in the yield of the target product.

[0077] Example 2: This example relates to the preparation of the five-membered azo compound III-2, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Alkenes are Under the same conditions, the target five-membered azo compound was prepared. The yield was 86%, and the dr ratio was 3.4:1.

[0078] 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.1 Hz, 2H), 7.49 - 7.43 (m,4H), 7.35 (t, J = 7.4 Hz, 2H), 7.30 - 7.24 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 4.28 (p, J = 7.8 Hz, 1H), 2.95 - 2.83 (m, 2H), 2.35- 2.28 (m, 1H), 2.29 (dd, J = 13.3, 8.3 Hz, 1H), 1.95 (ddt, J = 13.8, 9.2,6.9 Hz, 1H), 1.70 (dd, J = 13.2, 8.5 Hz, 1H).

[0079] 13 C NMR (101 MHz, CDCl3): δ 142.09, 140.01, 139.21, 133.21, 132.09,129.83, 128.90, 128.74, 127.8, 127.53, 127.36, 127.12, 125.38 (q, J = 279.7Hz), 97.70 (q, J = 26.0 Hz), 89.10, 34.63, 32.51, 31.62.

[0080] 19 F NMR (376 MHz, CDCl3): δ -73.68 (s).

[0081] Example 3: This example relates to the preparation of a five-membered azo compound III-3, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen ester compound to be 1:1. The only difference from Example 1 is that the olefin compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 86%, and the ratio of dr was 2.1:1.

[0082] 1H NMR (400 MHz, CDCl3): δ 7.20 (dd, J = 8.4, 5.5 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 4.51 (p, J = 7.7 Hz, 1H), 3.80 (s, 3H), 2.90 (dh, J = 14.1,7.1 Hz, 2H), 2.35 – 2.29 (m, 1H), 1.96 – 1.89 (m, 1H), 1.76 – 1.66 (m, 2H), 1.45 (s, 3H).

[0083] 13 C NMR (101 MHz, CDCl3): δ 171.82, 161.42 (d, J = 243.9 Hz), 136.65 (d, J = 3.5 Hz), 129.83 (d, J = 8.1 Hz), 115.29 (d, J = 21.4 Hz), 94.58,88.38, 52.87, 35.12, 34.07, 32.30, 21.29.

[0084] 19 F NMR (376 MHz, CDCl3): δ -117.15 (m).

[0085] Example 4: This example relates to the preparation of the five-membered azo compound III-4, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Alkenes are Under the same conditions, the target five-membered azo compound was prepared. The yield was 81%, and the ratio of dr to dr was 2.0:1.

[0086] 1H NMR (400 MHz, CDCl3): δ 7.28 - 7.11 (m, 5H), 4.83 - 4.71 (m, 1H), 3.94 -3.82 (m, 2H), 3.49 (dd, J = 13.8, 5.7 Hz, 1H), 2.76 (dd, J = 13.8, 8.9Hz, 1H), 1.90 (dp, J = 13.4, 6.7 Hz, 1H), 1.68 (dd, J = 13.0, 7.8 Hz, 1H), 1.54 (dd, J = 13.0, 8.3 Hz, 1H), 1.38 (s, 3H), 0.90 - 0.81 (m, 6H).

[0087] 13 C NMR (100 MHz, CDCl3): δ 171.4, 138.0, 129.4 (2C), 128.8 (2C), 126.8, 94.9, 90.7, 71.9, 39.3, 33.9, 27.9, 21.5, 19.2 (2C).

[0088] Example 5: This example relates to the preparation of a five-membered azo compound III-5, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 95%, and the ratio of dr to dr was 3.7:1.

[0089] 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.5Hz, 4H), 7.46 (t, J = 7.2 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.11 (s, 1H), 7.00(d, J = 8.1 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 4.55 (t, J = 8.7 Hz, 2H), 4.42(p, J = 7.8 Hz, 1H), 3.19 (t, J = 8.6 Hz, 2H), 2.94 (t, J = 7.7 Hz, 2H), 2.501 2.42 (m, 1H), 2.39 (dd, J = 13.1, 8.1 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.81 (dd, J = 13.1, 8.4 Hz, 1H).

[0090] 13 C NMR (101 MHz, CDCl3): δ 158.63, 142.02, 140.04, 133.38, 132.66,128.88, 127.89, 127.77, 127.55, 127.31, 127.12, 124.98, 124.48 (q, J = 282.1Hz), 109.16, 97.68 (q, J = 26.3 Hz), 89.33, 71.19, 35.23, 32.56, 31.64,29.77.

[0091] 19 F NMR (376 MHz, CDCl3): δ -73.66 (s).

[0092] Example 6: This example relates to the preparation of a five-membered azo compound III-6, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 84%, and the ratio of dr to dr was 2.3:1.

[0093] 1 H NMR (400 MHz, CDCl3): δ 8.12 (d,J = 8.5 Hz, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.7Hz, 2H), 7.60 (d, J = 8.4 Hz, 4H), 7.50 - 7.45 (m, 2H), 7.44 (d, J = 4.1 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 4.49 (p, J = 8.1 Hz, 1H), 3.66 -3.53 (m, 1H), 3.52 - 3.41 (m, 1H), 2.60 - 2.51 (m, 1H), 2.43 (dd, J = 13.2, 8.1 Hz, 1H),2.26 (ddt, J = 13.2, 9.5, 6.6 Hz, 1H), 1.85 (dd, J = 13.2, 8.5 Hz, 1H).

[0094] 13 C NMR (101 MHz, CDCl3): 140.06, 136.91, 134.01, 133.25, 131.74,128.90, 127.80, 127.57, 127.35, 127.18, 127.14, 126.31, 126.16, 125.70,125.58, 123.58, 97.70 (q, J = 26.7 Hz), 89.53, 34.08, 31.68, 30.33.

[0095] 19 F NMR (376 MHz, CDCl3): δ -73.58 (s).

[0096] Example 7: This example relates to the preparation of a five-membered azo compound III-7, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 82%, and the ratio of dr was 2.1:1.

[0097] 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.4 Hz, 2H), 7.60 - 7.56 (m,4H), 7.47 - 7.46 (m, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.41 -7.38 (m, 3H), 7.35- 7.31 (m, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 5.06 (s,2H), 4.41 (p, J = 7.7 Hz, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.52 - 2.43 (m, 1H), 2.38 (dd, J = 13.1, 8.1 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.81 (dd, J = 13.3, 8.6 Hz, 1H).

[0098] 13 C NMR (101 MHz, CDCl3): δ 157.36, 142.03, 140.06, 137.09, 133.35,133.06, 129.44, 128.88, 128.59, 127.95, 127.55, 127.47, 127.32, 127.13,124.47 (q, J = 282.1 Hz), 115.01, 97.69 (q, J = 26.0 Hz), 89.32, 70.07,34.94, 32.28, 31.64.

[0099] 19 F NMR (376 MHz, CDCl3): δ -73.67 (s).

[0100] Example 8: This example relates to the preparation of a five-membered azo compound III-8, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 75%, and the ratio of dr to dr was 2.3:1.

[0101] 1 H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 7.61 (d, J = 8.5 Hz, 3H),7.59 - 7.55 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 4.40(p, J = 8.3 Hz, 1H), 3.30 - 3.17 (m, 1H), 2.44 (s, 3H), 2.36 (dd, J = 15.0,6.8 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.94 (td, J = 14.4, 8.0 Hz, 1H), 1.80 (dd, J = 13.1, 8.6 Hz, 1H), 1.66-1.62 (m, 1H).

[0102] 13 C NMR (101 MHz, CDCl3): δ 149.41, 142.16, 139.98, 133.00, 130.08,128.88, 127.81, 127.48, 127.38, 127.12, 97.86 (q, J = 26.3 Hz), 88.67, 34.88,31.61, 23.81, 14.96.

[0103] 19 F NMR (376 MHz, CDCl3): δ -73.70 (s).

[0104] Example 9: This example relates to the preparation of a five-membered azo compound III-9, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 87%, and the ratio of dr to dr was 2.3:1.

[0105] 1 H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.7 Hz, 2H), 7.60 - 7.57 (m,4H), 7.46 (t, J = 7.6 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.20 - 7.12 (m, 1H), 7.00- 6.93 (m, 1H), 6.90 (d, J = 3.7 Hz, 1H), 4.46 (p, J = 7.8 Hz, 1H), 3.27 (t, J = 8.3 Hz, 2H), 2.53 (dq, J = 15.3, 7.6 Hz, 1H), 2.42 (dd, J = 13.2, 8.1 Hz, 1H), 2.13 (dt, J = 14.2, 7.6 Hz, 1H), 1.82 (dd, J = 13.2, 8.7 Hz, 1H).

[0106] 13 C NMR (101 MHz, CDCl3): δ 143.31, 142.07, 140.04, 133.21, 128.89,127.80, 127.55, 127.34, 127.13, 126.99, 124.90, 124.45 (q, J = 281.5 Hz), 123.60, 97.79 (q, J = 26.0 Hz), 88.99, 35.03, 31.54, 27.34.

[0107] 19F NMR (376 MHz, CDCl3): δ -74.32 (s).

[0108] Example 10: This example relates to the preparation of a five-membered azo compound III-10, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 86%, and the ratio of dr to dr was 2.6:1.

[0109] 1 H NMR (400 MHz, CDCl3): δ 7.63 - 7.60 (m, 2H), 7.59 - 7.56 (m, 4H), 7.48 - 7.43 (m, 2H), 7.42 - 7.36 (m, 1H), 7.02 - 6.95 (m, 2H), 6.87 - 6.81(m, 2H), 4.45(p, J = 7.5 Hz, 1H), 4.15 - 4.00 (m, 2H), 2.46 (dd, J = 13.2,7.9 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.25 - 2.18 (m, 1H), 2.15 - 2.06 (m, 2H),1.82 (dd, J = 13.1, 8.7 Hz, 1H).

[0110] 13 C NMR (101 MHz, CDCl3): δ 158.07, 156.48, 154.92, 142.09, 140.02,133.16, 128.88, 127.79, 127.52, 127.33, 127.12 (d, J = 2.6 Hz), 124.45 (d, J = 282.1 Hz), 115.90, 115.75, 115.45, 115.40, 97.55 (d, J = 26.0 Hz), 89.63,67.92, 31.77, 29.77, 26.80.

[0111] 19F NMR (376 MHz, CDCl3): δ -73.63 (s), -123.92 (s).

[0112] Example 11: This example relates to the preparation of a five-membered azo compound III-11, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen diboronate compound to be 1:1. The only difference from Example 1 is that the geminitrogen diboronate compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 86%, and the ratio of dr to dr was 1.9:1.

[0113] 1 H NMR (400 MHz, CDCl3): δ 7.64 - 7.59 (m, 2H), 7.58 (d, J = 8.2 Hz,5H), 7.47 - 7.43 (m, 2H), 7.41 -7.37 (m, 2H), 7.35 - 7.30 (m, 2H), 7.18 (d, J = 7.3 Hz, 1H), 6.58 (d, J = 17.3 Hz, 1H), 6.33 - 6.23 (m, 1H), 4.58 (p, J =8.2 Hz, 1H), 3.22 - 3.14 (m, 1H), 2.80 - 2.68 (m, 1H), 2.41 (dd, J = 13.1, 8.0 Hz, 1H), 1.90 (dd, J = 13.2, 8.7 Hz, 1H).

[0114] 13 C NMR (101 MHz, CDCl3): δ 142.07, 140.04, 136.85, 133.73, 133.50,128.88, 128.61, 127.78, 127.53, 127.34, 127.12, 126.21, 124.72, 124.44 (q, J = 282.0 Hz), 97.82 (q, J = 26.0 Hz), 89.54, 36.12, 31.10.

[0115] 19F NMR (376 MHz, CDCl3): δ -73.60 (s).

[0116] Example 12: This example relates to the preparation of a five-membered azo compound III-12, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen ester compound to be 1:1. The only difference from Example 1 is that the olefin compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 87%, and the ratio of dr to dr was 2.9:1.

[0117] 1 H NMR (400 MHz, CDCl3): δ 7.37 - 7.32 (m, 4H), 7.30 - 7.24 (m, 6H), 7.16 (dd, J = 8.7, 5.4 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 4.17 (p, J = 7.9Hz, 1H), 2.90 - 2.77 (m, 2H), 2.13 - 2.00 (m, 1H), 1.76 (d, J = 8.5 Hz, 2H), 1.67 (ddt, J = 13.8, 9.2, 6.8 Hz, 1H), 1.25 (s, 3H).

[0118] 13 C NMR (101 MHz, CDCl3): δ 171.53, 161.40 (d, J = 243.9 Hz), 142.82,136.80 (d, J = 3.1 Hz), 129.81 (d, J = 7.5 Hz), 129.14, 128.56, 127.52,115.33, 96.12, 86.39, 36.71, 34.77, 32.49, 22.71.

[0119] 19 F NMR (376 MHz, CDCl3): δ -117.20 (s).

[0120] Example 13: This example relates to the preparation of a five-membered azo compound III-13, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen ester compound to be 1:1. The only difference from Example 1 is that the olefin compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 90%, and the ratio of dr to dr was 2.2:1.

[0121] 1 H NMR (400 MHz, CDCl3): δ 8.21 (t, J = 8.2 Hz, 2H), 8.17 (d, J = 7.6Hz, 1H), 8.14 - 8.09 (m, 3H), 8.09 - 8.00 (m, 3H), 6.86 - 6.80 (m, 2H), 6.75(t, J = 8.7 Hz, 2H), 6.00 (d, J = 12.3 Hz, 1H), 5.86 (d, J = 12.3 Hz, 1H), 4.51 (p, J = 7.6 Hz, 1H), 2.60 (dt, J = 9.2, 6.0 Hz, 2H), 2.09 (ddt, J =14.0, 9.1, 6.9 Hz, 1H), 1.74 (ddt, J = 14.0, 8.8, 6.9 Hz, 1H), 1.64 – 1.55(m, 2H), 1.48 (s, 3H).

[0122] 13 C NMR (101 MHz, CDCl3): δ 171.07, 161.18 (d, J = 243.3 Hz), 136.43(d, J = 2.9 Hz), 131.90, 131.15, 130.59, 129.56, 129.48 (d, J = 7.5 Hz),128.31, 128.06, 127.99 (d, J = 4.0 Hz), 127.31, 126.15, 125.60 (d, J= 16.2Hz), 124.84, 124.57, 124.55, 122.75, 115.00 (d, J = 21.4 Hz), 94.84, 88.87,66.06, 34.88, 33.92, 31.92, 21.36.

[0123] 19 F NMR (376 MHz, CDCl3): δ -117.35 (m).

[0124] Example 14: This example relates to the preparation of a five-membered azo compound III-14, using tetrahydrofuran as the solvent and lithium diisopropylamino as the base reagent, and controlling the molar ratio of nitrous oxide to geminitrogen ester compound to be 1:1. The only difference from Example 1 is that the olefin compound is... Under the same conditions, the target five-membered azo compound was prepared. The yield was 89%, and the ratio of dr to dr was 1.6:1.

[0125] 1 H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.8Hz, 2H), 7.17 (dd, J = 7.8, 5.4 Hz, 2H), 7.00 - 6.95 (m, 3H), 6.89 (d, J =8.9 Hz, 1H), 6.66 (dd, J = 8.9, 2.0 Hz, 1H), 4.46 (p, J = 7.8 Hz, 1H), 4.43 -4.35 (m, 2H), 3.84 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 2.86 (t, J = 7.8 Hz,2H), 2.35 (s, 3H), 2.25 (dq, J = 14.2, 7.7 Hz, 1H), 1.83 (dq, J = 14.7, 7.9Hz, 1H), 1.68 (dd, J = 12.7, 8.2 Hz, 1H), 1.57 (dd, J= 12.8, 8.1 Hz, 1H),1.41 (s, 3H).

[0126] 13 C NMR (101 MHz, CDCl3): δ 171.42, 168.27, 161.41 (d, J = 243.9 Hz),156.02, 139.20, 136.61 (d, J = 2.6 Hz), 135.37, 133.91, 131.15, 130.88,130.76, 129.82 (d, J = 8.1 Hz), 129.11, 115.28 (d, J = 20.8 Hz), 115.04,114.79, 111.51, 101.04, 94.48, 88.29, 64.62, 55.73, 35.01, 34.15, 32.31,23.54, 21.16, 13.35.

[0127] 19 F NMR (376 MHz, CDCl3): δ -117.10 (m).

[0128] Application Example 1: Taking the five-membered azo compound III-1 prepared in Example 1 as an example, it was used to prepare cyclopropane compounds. The details are as follows:

[0129] Under a nitrogen atmosphere, a pentazo compound III-1 (0.2 mmol), along with the solvent tetrahydrofuran (2.0 mL) and a photosensitizer (0.02 mmol), was added to a 10 mL Shrek flask. The reaction was then carried out under 420 nm light for 12 hours. The reaction was monitored by TLC, and the target product (80%, dr 2.5:1) was obtained by column chromatography.

[0130] 1 H NMR (400 MHz, CDCl3): δ 7.65 - 7.59 (m, 3H), 7.59 - 7.54 (m, 2H), 7.54 - 7.46 (m, 4H), 7.23 (dd, J = 8.1, 5.9 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 2.88 (dddd, J= 29.8, 14.0, 9.2, 6.4 Hz, 2H), 2.71 (qdd, J = 14.1, 9.0,6.5 Hz, 1H), 2.14 (dq, J = 14.8, 6.5 Hz, 1H), 1.40 (p, J = 7.4 Hz, 1H), 1.36- 1.33 (m, 1H), 1.29 - 1.25 (m, 1H).

[0131] 19 F NMR (376 MHz, CDCl3): δ -61.95 (s), -117.15 (m).

[0132] 13 C NMR (101 MHz, CDCl3): δ 162.20, 160.58, 140.82 (d, J = 80.3 Hz), 137.25 (d, J = 3.3 Hz), 136.81, 132.18, 131.36, 129.83, 129.78, 128.83,127.51, 127.10, 115.19 (d, J = 21.0 Hz), 35.10, 31.74, 29.70, 25.22, 16.03.

[0133] Application Example 2: Taking the five-membered azo compound III-1 prepared in Example 1 as an example, it was used to prepare 1,3-diamine compounds. The details are as follows:

[0134] Under a nitrogen atmosphere, tetrahydrofuran (2.0 mL), lithium aluminum hydride (2.0 mmol), and titanium tetrachloride (0.2 mmol) were added to a 10 mL Shrek flask. After stirring for 15 minutes, the pentavalent azo compound III-1 (0.2 mmol) was added. The reaction was carried out for 12 hours and monitored by TLC. The target product (70%, dr1.1:1) was obtained by column chromatography.

[0135] 1 H NMR (400 MHz, CDCl3): δ 7.77 - 7.53 (m, 6H), 7.41 - 7.31 (m, 2H), 6.99 (ddd, J= 8.6, 5.4, 2.6 Hz, 1H), 6.93 - 6.78 (m, 2H), 2.61 - 2.55 (m,1H), 2.49 (d, J = 7.9 Hz, 2H), 2.33 (dd, J = 14.4, 1.9 Hz, 1H), 2.08 - 1.80 (m, 7H), 1.69 - 1.51 (m, 2H).

[0136] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A method for preparing pentazocine compounds mediated by nitrous oxide, characterized in that, Includes the following steps: Under a protective atmosphere, S1. The geminiboronic acid ester compound shown in Formula I is reacted with nitrous oxide in the presence of a solvent and an alkaline reagent to obtain an intermediate product; S2. Add the olefin compound shown in Formula II to the above reaction system containing the intermediate product and continue the reaction to obtain the five-membered azo compound shown in Formula III. The structures of equations I, II, and III above are shown below: ， Wherein, R is a substituted or unsubstituted alkyl group, and the substituent of the substituted alkyl group is selected from one or more of the following groups: phenyl, halogenated and / or alkyl-substituted phenyl, benzyloxy-substituted phenyl, heteroaryl, halogenated and / or alkyl-substituted heteroaryl, heterocyclophenyl, halogenated and / or alkyl-substituted heterocyclophenyl, naphthyl, halogenated or alkyl-substituted naphthyl, halophenoxy, styryl. R1 is selected from alkyl or haloalkyl; R2 is selected from aryl, NPh2C(O)-, and R'OC(O)-; R' is selected from alkyl, aryl, and aryl-substituted alkyl.

2. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, In step S1, the geminoboronic acid ester compound shown in Formula I is first dissolved in a solvent, and an alkaline reagent is added dropwise to carry out a first reaction. Then, nitrous oxide is introduced to carry out a second reaction to obtain an intermediate product.

3. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 2, characterized in that, The temperature of the first reaction is 0-5 °C, and the reaction time is 0.5-1 h. And / or, the temperature of the secondary reaction is 10-40 °C, and the time of the secondary reaction is 1-4 h.

4. A method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1 or 2, characterized in that, In step S1, the molar ratio of the geminolate ester compound to nitrous oxide is 1:(1-3), and the nitrous oxide concentration in the reaction vessel is less than 1 atm. And / or, the molar ratio of the geminitrogenate compound represented by Formula I to the volume of solvent added is 0.1-0.2 mol / L.

5. A method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1 or 2, characterized in that, In step S1, the solvent is selected from one or more of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether, dimethyl ether, and benzene.

6. A method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1 or 2, characterized in that, In step S1, the alkaline reagent is lithium diisopropylamino and / or lithium tetramethylpiperidine.

7. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, In step S2, the molar ratio of the olefin compound represented by Formula II to the geminoboronate compound represented by Formula I is 1:(1.5-2.5).

8. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, In step S2, the reaction temperature is 10-40 °C and the reaction time is 2-4 h.

9. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, R is selected from C 1-6 Alkyl, phenyl substituted C 1-6 Alkyl, halophenyl substituted C 1-6 Alkyl, dihydrofuranophenyl-substituted C 1-6 Alkyl, naphthyl substituted C 1-6 Alkyl, benzyloxyphenyl substituted C 1-6 Alkyl, thiazolyl substituted C 1-6 Alkyl, alkyl-substituted thiazolyl-substituted C 1-6 Alkyl, thiophene-substituted C 1-6 Alkyl, halophenoxy substituted C 1-6 Alkyl, styrene-substituted C 1-6 One of the alkyl groups; And / or, R1 is selected from C 1-6 Alkyl, Halogenated C 1-6 One of the alkyl groups; And / or, R2 is selected from biphenyl, NPh2C(O)-, , One of them.

10. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, The geminodic diborate esters represented by Formula I are selected from one of the compounds shown in the following structures: ； And / or, the olefin compound represented by Formula II is selected from one of the compounds shown in the following structures: 。 11. The method for preparing pentazocine compounds mediated by nitrous oxide according to claim 1, characterized in that, The five-membered azo compounds include compounds with the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 。

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