CN116731051A - A method for synthesizing cis 2-alkyl-3-boryl heterocyclic compounds - Google Patents

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a cis-2-alkyl-3-boron heterocyclic compound, which has the following reaction formula:

Description

A method for synthesizing cis 2-alkyl-3-boryl heterocyclic compounds

Technical field

The present invention relates to the technical field of organic synthesis, and specifically relates to a method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds.

Background technique

2,3-Disubstituted heterocyclic organic compounds widely exist in natural products and pharmaceutical molecules [a) Y.Takahashi, H.Fuwa, A.Kaneko, M.Sasaki, S.Yokoshima, H.Koizumi, T.Takebe ,T.Kan,T.Iwatsubo,T.Tomita,H.Natsugari,T.Fukuyama,Bioorg.Med.Chem.Lett.2006,16 3813-3816;b)F.J.Urban,B.S.Moore,Bioorg.J.Heterocyclic Chem .1992, 29, 431-438; c) T. Harrison, B. J. Williams, C. J. Swain, R. G. Ball, Bioorg. Med. Chem. 1994, 4, 2545-2550; d) D. R. W. Jayne, A. N. Bruchfeld, L. Harper, M. Schaier,M.C.Venning,P.Hamilton,V.Burst,F.Grundmann,M.Jadoul,I.Szombati,V.Tesar,M.Segelmark,A.Potarca,T.J.Schall,P.Bekker,J.Am.Soc. Nephrol.2017,28,2756-2767].

Based on the important application of this fragment in natural products and drugs, the current method for synthesizing 2,3-disubstituted heterocyclic organic compounds: [a) Z.Y.Yang, H.Luo, M.Zhang, X.C.Wang, ACS Catal.2021 ,11,10824-10829;b)T.K.Beng,H.Takeuchi,M.Weberc,R.Sarpong,Chem.Commun.2015,51,7653-7656;c)M.P.Paudyal,M.Wang,J.H.Siitonen,Y. Hu, M. Yousufuddin, H.C. Shen, J.R. Falck, L. Kürti, Org. Biomol. Chem., 2021, 19, 557; d) P. Duan, H. Zhao, J. Yang, L. Cao, H. F. Jiang, M. Zhang,Org.Lett.2022,24,608-612;e)C.Xu,R.Cheng,Y.C.Luo,M.K.Wang,X.G.Zhang,Angew.Chem.,Int.Ed.2020,59,18741-18747], now Methods for constructing such compounds usually require multi-step reactions, which are cumbersome and cannot effectively control stereoselectivity; or are limited by raw materials and have an extremely limited substrate range, which does not meet the diversity of chemical synthesis and cannot meet the requirements of modern high-throughput The need for drug screening.

Therefore, the study is looking for a reaction with simple steps, a wide and easily available substrate range, high regioselectivity and stereoselectivity, and the introduction of boron-containing functional groups, which can efficiently synthesize 2-alkyl-3-boron heterocyclic compounds. method appears to be necessary.

Contents of the invention

The object of the present invention is to provide a method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds, which has simple reaction steps, a wide range of substrates and is easily available, has high regioselectivity and stereoselectivity, and introduces With the addition of boron-containing functional groups, 2-alkyl-3-boron heterocyclic compounds can be synthesized efficiently.

The scheme adopted by the present invention to achieve the object is: a method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds, and a reaction formula for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds. As follows:

The compound of formula 2, the compound of formula 3 and the compound of formula 4 are reacted under the action of nickel salt catalyst, ligand and base, or the compound of formula 2, compound of formula 3 and compound of formula 4 are reacted under the action of nickel salt catalyst, ligand, base and additives. The reaction is carried out under the action of , to obtain a compound of formula 1; the compound shown in formula 3 is a diboron reagent;

The structural formula of the 2-alkyl-3-boryl heterocyclic compound is shown in the following formula 1;

Among them, n is selected from 0 or 1; Y is selected from any one of O and NPG, PG is selected from any one of Cbz and Boc, X is selected from one of bromine atoms and chlorine atoms, and Ar is selected from halogen At least one of a substituted aryl group, a methoxy-substituted aryl group, and a trifluoromethoxy-substituted aryl group, [B] represents a boron functional group.

Preferably, in the nickel salt catalyst, the cation is Ni ⁺ and the anion is selected from Cl ^– , Br ^– , I ^– , [CH ₃ COO] ^– ,

At least one of [CF ₃ COO] ^– , [acac] ^– and dibenzylideneacetone.

Preferably, the cation of the base is selected from at least one of Li ⁺ , Na ⁺ , K ⁺ and Cs ⁺ ; the anion of the base is selected from F ^– , CO ₃ ^2– , [CH ₃ COO] ^– , [ CF ₃ COO] ^– , [OMe] ^– and [O ^t Bu] ^– at least one.

Preferably, the additive is a salt, the cation of the salt is at least one of Li ⁺ , Na ⁺ , K ⁺ , Cs ⁺ and Mg ²⁺ ; the anion of the salt is selected from F ^– , Cl ^– , Br At least one of ^– , I ^– and SO ₄ ^2– .

Preferably, the ligand is selected from any one of the following compounds:

Among them, R ¹ is selected from one of trifluoromethyl and tert-butyl; R ² is selected from one of 1-naphth and 3,5- ^tBu -C ₆ H ₃ .

Preferably, the compound of formula 3 is selected from one or more of the following compounds:

Preferably, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, N-methylpyrrolidone, N,N-dimethylformamide, One or more of N,N-dimethylacetamide and 1,2-dichloroethane.

Preferably, the molar ratio of the compound represented by Formula 2, the compound represented by Formula 3 and the compound represented by Formula 4 is 1:(2.0～2.5):(2.0～2.5).

Preferably, the molar ratio of the nickel salt catalyst, ligand, base, additive and compound represented by Formula 2 is (0.03~0.15):(0~0.15):(1.0~3.0):(0~1.0):1 .

When Y is NPG, the reaction does not require the addition of additional ligands.

Compared with the existing technology, the present invention has the following advantages and beneficial effects:

1. The present invention provides a method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds, which uses heterocyclic olefins, alkyl halides and diboron reagents, under the action of nickel salt catalyst, in one pot. cis-2-alkyl-3-boron heterocyclic compounds are prepared by the method. This method can not only efficiently synthesize the target compound, but also has mild reaction conditions, strong substrate applicability, good functional group compatibility, and excellent regional selection. sex and stereoselectivity.

2. The method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds provided by the present invention uses cheap and readily available raw materials, is easy to operate, and can efficiently synthesize 2-alkyl-3-boryl heterocyclic compounds. compounds.

3. The method for synthesizing cis-2-alkyl-3-boryl heterocyclic compounds provided by the present invention contains boron groups in the synthesized products. The target compound can be further stereoselectively transformed, and other functionalized compounds can be synthesized simply and efficiently. 2,3-Disubstituted heterocyclic organic compounds provide new methods for the synthesis of complex drug molecules and drug lead compounds.

Detailed ways

In order to better understand the present invention, the following examples further illustrate the present invention, but the content of the present invention is not limited to the following examples.

In the following examples, B ₂ pin ₂ refers to pinacol diborate; NiCl ₂ ·DME refers to bis(ethylene glycol dimethyl ether) nickel chloride, LiOMe refers to lithium methoxide, KI refers to potassium iodide, and DMA is Refers to N,N-dimethylacetamide, and DCE refers to 1,2-dichloroethane. L represents the ligand, and the ligand is selected from one of the following compounds:

Among them, R ¹ is selected from one of CF ₃ and ^t Bu; R ² is selected from one of 1-naphth and 3,5- ^t Bu-C ₆ H ₃ .

Specifically, L1～L6 respectively represent the following ligands:

Example 1

The reaction formula for preparing 2-alkyl-3-boryl heterocyclic compounds is as follows:

According to the above reaction formula, the common reaction conditions in schemes 1 to 9 in Table 1 below are: compound 2a (1.0equiv), compound 3a (1.5equiv), compound 4a (1.5equiv), NiCl ₂ ·DME (6mol%), L (6mol%), LiOMe (1.5equiv), DMA, 50℃, 24h;

Condition b: Change the equivalents of compounds 3a, 4a and base, sequentially changing to compound 3a (1.0mmol, 2.5equiv), compound 4a (1.0mmol, 2.5equiv), LiOMe (1.0mmol, 2.5equiv);

Condition c: Change the equivalents of compounds 3a, 4a, base and NiCl ₂ ·DME to compound 3a (0.8mmol, 2.0equiv), compound 4a (0.8mmol, 2.0equiv), LiOMe (1.0mmol, 2.5equiv), NiCl ₂ ·DME (5mol%);

Condition d: Add additive KI (1.0equiv).

Optional materials for nickel salt catalysts are NiBr ₂ ·DME, NiCl ₂ ·DME, and NiI _2. Changing the type of catalyst has little impact on the reaction, so they are not listed one by one. The temperature range is 30°C to 80°C. Changing the temperature has little effect on the reaction, so other temperatures are not listed one by one. When Y is NPG, no additional ligand is required for the reaction.

The yield and dr at different ligands, solvents, and temperatures are shown in Table 1 below:

Table 1 Yields and rr of different ligands and solvents

Example 2

In a glove box filled with argon, add bis(ethylene glycol dimethyl ether) nickel chloride (5.3 mg, 0.024 mmol), L1 (5.0 mg, 0.024 mmol), lithium methoxide (38.0 mg, 1.0 mmol) and Pinacol borate (254.0 mg, 1.0 mmol) was dissolved in 1 mL of dry N,N-dimethylacetamide solvent, and then 3,4-dihydro-2H-pyran (31 μL, 0.4 mmol) and 4 were added -Trifluoromethoxybenzyl bromide (255.0 mg, 1.0 mmol), then add 1 mL of dry N,N-dimethylacetamide, seal the reaction tube and take it out of the glove box, react at 30°C for 24 hours . After the reaction is completed, the reaction solvent is concentrated under reduced pressure, and the product is separated and purified by column chromatography to obtain the product 4,4,5,5-tetramethyl-2-((2R,3R)-2-(4-(trifluoromethoxy)benzyl)tetrahydro-2H -pyran-3-yl)-1,3,2-dioxaborolane (white solid, yield 86%, dr>20:1). ¹ HNMR(600MHz,Chloroform-d)δ7.27(dd,J＝8.6,2.0Hz,2H),7.14-7.06(m,2H),4.03-3.97(m,1H),3.57(ddd,J＝7.5 ,6.3,2.8Hz,1H),3.41(td,J＝11.6,2.6Hz,1H),3.03(dd,J＝13.9,7.6Hz,1H),2.87(dd,J＝13.9,6.3Hz,1H) ,1.99-1.92(m,1H),1.78-1.70(m,1H),1.63-1.56(m,1H),1.44-1.40(m,1H),1.30(s,12H),1.23-1.20(m, 1H)ppm; ¹³ C NMR (151MHz, Chloroform-d) δ 147.6, 138.7, 130.7, 120.8, 120.7 (q, J = 256.4Hz), 83.2, 81.3, 69.0, 40.7, 26.2, 25.1, 25.0, 24.9; ¹¹ B NMR(193MHz,Chloroform-d)δ33.25ppm; ¹⁹ F NMR(376MHz,Chloroform-d)δ-57.73ppm; HRMS(ESI)calculated[M+H] ⁺ for C ₁₉ H ₂₇ BF ₃ O ₄ ⁺ =387.1949 ,found:387.1942.

Example 3

In a glove box filled with argon, add bis(ethylene glycol dimethyl ether) nickel chloride (5.3 mg, 0.024 mmol), L1 (5.0 mg, 0.024 mmol), lithium methoxide (38.0 mg, 1.0 mmol) and Pinacol borate (254.0 mg, 1.0 mmol) was dissolved in 1 mL of dry N,N-dimethylacetamide solvent, and then 3,4-dihydro-2H-pyran (31 μL, 0.4 mmol) and 3 were added , 4,5-trifluorobenzyl bromide (225.0mg, 1.0mmol), then add 1mL of dry N,N-dimethylacetamide, seal the reaction tube and remove it from the glove box, react at 30°C for 24 Hour. After the reaction is completed, the reaction solvent is concentrated under reduced pressure, and the product is separated and purified by column chromatography to obtain the product 4,4,5,5-tetramethyl-2-((2R,3R)-2-(3,4,5-trifluorobenzyl)tetrahydro- 2H-pyran-3-yl)-1,3,2-dioxabor olane (colorless oily liquid, yield 47%, dr>20:1). ¹ H NMR (600MHz, Chloroform-d) δ6.98-6.79 (m, 2H), 4.01-3.96 (m, 1H), 3.52 (ddd, J = 8.3, 5.7, 2.8Hz, 1H), 3.40 (td, J＝11.6,2.6Hz,1H),2.99(dd,J＝14.2,8.2Hz,1H),2.77(dd,J＝14.0,5.7Hz,1H),2.00-1.95(m,1H),1.78-1.70 (m,1H),1.63-1.57(m,1H),1.45-1.41(m,1H),1.30(s,12H),1.20-1.17(m,1H)ppm; ¹³ C NMR(151MHz,Chloroform-d )δ151.8(dd,J＝9.8,4.0Hz),150.1(dd,J＝9.7,4.2Hz),139.1(t,J＝15.3Hz),137.5(t,J＝15.4Hz),136.3(dt , J=7.3, 3.6Hz), 113.2 (dd, J=16.4, 4.2Hz), 83.3, 80.9, 69.0, 40.6, 26.1, 25.1, 25.0, 24.9ppm; ¹¹ B NMR (193MHz, Chloroform-d) δ33. 61ppm; ¹⁹ FNMR (565MHz, Chloroform-d) δ -135.86, -164.85ppm; HRMS (ESI) calculated [M+H] ⁺ for C ₁₈ H ₂₅ BF ₃ O ₃ ⁺ = 357.1843, found: 357.1840.

Example 4

In a glove box filled with argon, add bis(ethylene glycol dimethyl ether) nickel chloride (5.3 mg, 0.024 mmol), L1 (5.0 mg, 0.024 mmol), lithium methoxide (38.0 mg, 1.0 mmol) and Pinacol borate (254.0 mg, 1.0 mmol) was dissolved in 1 mL of dry N,N-dimethylacetamide solvent, and then 4H-chromene (52.9 mg, 0.4 mmol) and benzyl bromide (171.0 mg, 1.0 mmol) were added ), then add 1 mL of dry N,N-dimethylacetamide, seal the reaction tube and take it out of the glove box, and react at 30°C for 24 hours. After the reaction is completed, the reaction solvent is concentrated under reduced pressure, and the product is separated and purified by column chromatography to obtain the product 2-((2R,3R)-2-benzylchroman-3-yl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (white solid, yield 73%, dr>20:1). ¹ H NMR (600MHz, Chloroform-d) δ7.34-7.26 (m, 2H), 7.23-7.19 (m, 3H), 7.10-7.05 (m, 2H), 6.83 (td, J＝7.4, 1.2Hz, 1H),6.78(dd,J＝8.1,1.2Hz,1H),4.55(dt,J＝9.1,3.9Hz,1H),3.03(dd,J＝13.8,9.2Hz,1H),2.92(dd,J ＝16.6,9.9Hz,1H),2.86-2.80(m,2H),1.78(ddd,J＝9.7,6.0,3.4Hz,1H),1.25(d,J＝6.1Hz,12H)ppm; ¹³ C NMR (101MHz, Chloroform-d) δ153.8,139.4,129.7,129.5,128.4,127.3,126.3,122.5,119.9,117.4,83.7,78.0,38.5,25.0,24.8,24.5ppm; ¹¹ B NMR (193MHz, Chloroform -d) δ32.87ppm; HRMS(ESI)calculated[M+H] ⁺ for C ₂₂ H ₂₈ BO ₃ ⁺ =351.2126, found: 351.2134.

Example 5

In a glove box filled with argon, add bis(ethylene glycol dimethyl ether) nickel chloride (5.3 mg, 0.024 mmol), L1 (5.0 mg, 0.024 mmol), lithium methoxide (38.0 mg, 1.0 mmol) and Pinacol borate (254.0 mg, 1.0 mmol) was dissolved in 1 mL of dry N,N-dimethylacetamide solvent, and then 2,3-dihydrofuran (28.0 mg, 0.4 mmol) and benzyl bromide (171.0 mg, 1.0 mmol), then add 1 mL of dry N,N-dimethylacetamide, seal the reaction tube and take it out of the glove box, and react at 30°C for 24 hours. After the reaction is completed, the reaction solvent is concentrated under reduced pressure, and the product is separated and purified by column chromatography to obtain the product 2-((2R,3R)-2-benzyltetrahydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (white solid, yield 77%, dr>20:1). ¹ H NMR (600MHz, Chloroform-d) δ7.29-7.23 (m, 4H), 7.20-7.16 (m, 1H), 4.34 (ddd, J＝9.9, 7.7, 3.6Hz, 1H), 4.00 (ddd, J＝8.1,6.8,5.2Hz,1H),3.67(q,J＝7.8Hz,1H),2.83(dd,J＝13.8,3.6Hz,1H),2.71(dd,J＝13.8,9.9Hz,1H ), 2.01 (ddd, J＝8.8, 7.1, 5.1Hz, 2H), 1.78 (q, J＝8.5Hz, 1H), 1.28 (d, J＝5.6Hz, 12H)ppm; ¹³ C NMR (151MHz, Chloroform -d)δ140.0,129.2,128.4,126.1,83.6,81.6,67.9,40.5,28.2,25.1,25.0ppm; ¹¹ B NMR (193MHz, Chloroform-d)δ33.66ppm; HRMS(ESI)calculated[M+H] ⁺ for C ₁₇ H ₂₆ BO ₃ ⁺ =289.1969,found:289.1967.

Example 6

In a glove box filled with argon, add bis(ethylene glycol dimethyl ether) nickel chloride (4.4 mg, 0.02 mmol), lithium methoxide (38.0 mg, 1.0 mmol), potassium iodide (66.4 mg, 0.4 mmol) and Pinacol borate (203.2 mg, 0.8 mmol) was dissolved in 1 mL of dry 1,2-dichloroethane solvent, and then benzyl 3,4-dihydropyridine-1(2H)-carboxylate (87.0 mg, 0.4 mmol) was added and 3,4-dichlorobenzyl bromide (239.9 mg, 1.0 mmol), then add 1 mL of dry 1,2-dichloroethane, seal the reaction tube and take it out of the glove box, react at 50°C for 24 hours . After the reaction is completed, the reaction solvent is removed by concentrating under reduced pressure. Then dissolve it in tetrahydrofuran/water (6mL, 2:1), add NaBO ₃ ·4H ₂ O (246.2mg, 1.6mmol), react at room temperature for 4 hours, quench with saturated sodium chloride, extract, dry, and reduce pressure Concentrate to remove the solvent. The product benzyl(2R,3R)-2-(3,4-dichlorobenzyl)-3-hydroxypiperidine-1-carboxylate (yellow solid, yield 31%, dr>20:1) was obtained through column chromatography separation and purification. ¹ H NMR(600MHz,Chloroform-d)δ7.35-7.26(m,3H),7.26-7.20(m,2H),7.20-6.99(m,2H),6.99-6.88(m,1H),5.06- 4.73(m,2H),4.69-4.46(m,1H),4.18-3.98(m,1H),3.85(dt,J＝11.0,5.0Hz,1H),3.01-2.95(m,1H),2.87( td,J＝13.3,3.0Hz,1H),2.75(dd,J＝14.3,11.2Hz,1H),1.88-1.82(m,1H),1.78-1.72(m,1H),1.67-1.60(m, 1H), 1.53 (qt, J = 12.7, 3.9Hz, 1H) ppm; ¹³ C NMR (151MHz, Chloroform-d) δ 155.5, 139.5, 132.2, 131.1, 130.3, 130.2, 128.7, 128.6, 128.2, 127.9, 69.1, 67.4, 57.4, 38.0, 28.9, 27.9, 24.3ppm; HRMS (ESI) calculated [M+H] ⁺ for C ₂₀ H ₂₂ Cl ₂ NO ₃ ⁺ =394.0971, found: 394.0977.

The synthesis of 2-alkyl-3-boryl heterocyclic compounds in the following Examples 7 to 9 is carried out with reference to the method steps of the above-mentioned Example 2. The 2-alkyl-3-boryl heterocyclic compounds in Example 10 The oxidation was carried out with reference to the method steps of Example 6. In the compound 4Ar-X used in Examples 7 to 10, X is Br. The structure and name of the synthesized compound, NMR, HRMS data and yield are shown in Table 2 below:

Table 2 Examples 7 to 10 product structure, name, NMR, HRMS and yield

The above are only preferred embodiments of the present invention. Of course, they cannot be used to limit the scope of rights of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principles of the present invention, they can also Several improvements and changes are made, and these improvements and changes are also considered to be within the protection scope of the present invention.

Claims (9)

1. A method for synthesizing cis-2-alkyl-3-boron heterocyclic compounds is characterized in that: the reaction formula for synthesizing the cis-2-alkyl-3-boron heterocyclic compound is shown as follows:

reacting the compound shown in the formula 2, the compound shown in the formula 3 and the compound shown in the formula 4 under the action of a nickel salt catalyst, a ligand and alkali or reacting the compound shown in the formula 2, the compound shown in the formula 3 and the compound shown in the formula 4 under the action of the nickel salt catalyst, the ligand, the alkali and an additive to obtain the compound shown in the formula 1; the compound shown in the formula 3 is a boron-linked reagent;

wherein the structural formula of the 2-alkyl-3-boron heterocyclic compound is shown as the following formula 1;

wherein n is taken from 0 or 1; y is selected from any one of O, NPG, PG is selected from any one of Cbz and Boc, X is selected from one of bromine atom and chlorine atom, ar is selected from at least one of halogen substituted aryl, methoxy substituted aryl and trifluoromethoxy substituted aryl, and [ B ] represents boron functional group.

2. The method for synthesizing cis-2-alkyl-3-boron-based heterocyclic compound according to claim 1, wherein the cation in the nickel salt catalyst is Ni ⁺ The anion being selected from Cl ^– 、Br ^– 、I ^– 、[CH ₃ COO] ^– 、[CF ₃ COO] ^– 、[acac] ^– And dibenzylidene acetone.

3. The method for synthesizing cis-2-alkyl-3-boro-heterocycles according to claim 1, wherein the cation of the base is selected from the group consisting of Li ⁺ 、Na ⁺ 、K ⁺ And Cs ⁺ At least one of (a) and (b); the anion of the base is selected from F ^– 、CO ₃ ^2– 、[CH ₃ COO] ^– 、[CF ₃ COO] ^– 、[OMe] ^– And [ O ] ^t Bu] ^– At least one of them.

4. The method for synthesizing cis-2-alkyl-3-boron-based heterocyclic compound according to claim 1, wherein the additive is a salt, and the cation of the salt is Li ⁺ 、Na ⁺ 、K ⁺ 、Cs ⁺ And Mg (magnesium) ²⁺ At least one of (a) and (b); the anions of the salt being selected from F ^– 、Cl ^– 、Br ^– 、I ^– And SO ₄ ^2– At least one of them.

5. The method for synthesizing cis-2-alkyl-3-boron-based heterocyclic compounds according to claim 1, wherein the ligand is selected from any one of the following compounds:

wherein R is ¹ One selected from trifluoromethyl and tert-butyl; r is R ² Selected from 1-naphth, 3,5- ^t Bu-C ₆ H ₃ One of them.

6. The method of synthesizing cis-2-alkyl-3-boro-heterocycles according to claim 1, wherein the compound of formula 3 is selected from one or more of the following:

7. the method for synthesizing cis-2-alkyl-3-boro-heterocycles according to claim 1, wherein the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tertiary butyl ether, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide and 1, 2-dichloroethane.

8. The method for synthesizing a cis-2-alkyl-3-boron-based heterocyclic compound according to claim 1, wherein the molar ratio of the compound represented by formula 2, the compound represented by formula 3 to the compound represented by formula 4 is 1 (2.0 to 2.5): 2.0 to 2.5.

9. The method for synthesizing cis-2-alkyl-3-boron-based heterocyclic compounds according to claim 1, wherein the molar ratio of the nickel salt catalyst, ligand, base, additive to the compound represented by formula 2 is (0.03-0.15): 0-0.15): 1.0-3.0: (0-1.0): 1.