Method for Stereoselectively Preparing 2-Alkyl-4-Boryl Heterocyclic Compounds

Abstract

The present invention provides a method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds. The structural formula of the 2-alkyl-4-boryl heterocyclic compounds is shown as Formula 1 below: The reaction formula for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds is shown as follows: This method uses an alkene, an alkyl halide, and a diboron reagent, and under the action of a metal nickel catalyst, a one-pot reaction is carried out to prepare cis-2-alkyl-4-boryl heterocyclic compounds. It has a high yield, mild reaction conditions, strong substrate applicability, good functional group compatibility, excellent regioselectivity and stereoselectivity; the raw materials used are cheap and easily available, the operation is simple, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds. Background Art

[0002] 2,4-Disubstituted heterocyclic organic compounds are widely present in natural products and drug molecules [a) C.F. Sturino, D. Rajotte, Y. Bousquet, Bioorg. Med. Chem. Lett. 2013, 23, 3967 - 3975; b) P.S. Watson, B. Jiang, K. Harrison, N. Asakawa, P.K. Welch, Bioorg. Med. Chem. Lett. 2006, 16, 5695 - 5699. c) L. Cheng, B. Ohlsson, P. Schell, M. Karle, D. Pettersen, ACS Med. Chem. Lett. 2014, 5, 538 - 543. d) S.J. Veenstra, K. Hauser, W. Schilling, C. Betschart, S. Ofner, Bioorg. Med. Chem. Lett, 1996, 6, 3029 - 3034. e) R.W. Hoffmann, A. Endesfelder, Liebigs. Ann. Chem. 1986, 12, 1823 - 1836. f) A. Burtea, J. DeForest, X. Li, S.D. Rychnovsky, Angew. Chem. Int. Ed. 2019, 58, 16193 - 16197. g) A.X. Gao, T. Hamada, S.A. Snyder, Angew. Chem. Int. Ed. 2016, 55, 10301 - 10306. h) P. Bhutani, G. Joshi, N. Raja, N. Bachhav, P.K. Rajanna, H. Bhutani, A.T. Paul, R. Kumar, J. Med. Chem. 2021, 64, 2339 - 2381].

[0003] Based on the important applications of this fragment in natural products and drugs, the current methods for synthesizing 2,4-disubstituted heterocyclic organic compounds are as follows: [a) F. Guo, R. C. Dhakal, R. K. Dieter, J. Org. Chem. 2013, 78, 8451 - 8464. b) G. Chambournier, R. E. Gawley, Org. Lett. 2000, 11, 1561 - 1564. c) F. K. I. Chio, S. J. J. Guesné, L. Hassall, T. McGuire, A. P. Dobbs, J. Org. Chem. 2015, 80, 9868 - 9880. d) M. Duplessis, L. Morency, C. James, J. Minville, P. Deroy, Tetrahedron Letters. 2013, 54, 2303 - 2307. e) P. Beak, W. K. Lee, J. Org. Chem. 1990, 55, 2578 - 2580. f) P. Celestini, B. Danieli, G. Lesma, A. Sacchetti, A. Silvani, D. Passarella, A. Virdis, Org. Lett. 2002, 8, 1367 - 1370. h) J. S. Yadav, B. V. Subba Reddy, G. G. K. S. N. Kumar, S. Aravind, Synthesis, 2008, 3, 395 - 400]. The existing methods for constructing such compounds usually require multiple steps, the procedures are relatively cumbersome, and the stereoselectivity cannot be effectively controlled; or they are restricted by raw materials, the substrate scope is extremely limited, which does not conform to the diversity of chemical synthesis and cannot meet the requirements of modern high-throughput drug screening.

[0004] Therefore, it is necessary to study and find a method with simple reaction steps, a wide and easily accessible substrate scope, high regioselectivity and stereoselectivity, and introducing boron-containing functional groups to efficiently synthesize 2-alkyl-4-boryl heterocyclic compounds. SUMMARY OF THE INVENTION

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to some extent. In the first aspect of the present invention, the present invention provides a method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds, and the structural formula of the 2-alkyl-4-boryl heterocyclic compounds is shown as Formula 1 below:

[0006]

[0007] Among them, n is taken from 0, 1; Y is selected from one of O, N and NPG, where PG is a protecting group; Alkyl represents an alkyl substituent, and [B] represents a boron functional group;

[0008] The reaction formula for the stereoselective preparation of 2-alkyl-4-boryl heterocyclic compounds is as follows:

[0009]

[0010] A method for the stereoselective preparation of 2-alkyl-4-boryl heterocyclic compounds, comprising: reacting a compound of formula 2, a compound of formula 3 and a compound of formula 4 under the action of a nickel salt catalyst, a diamine ligand and a base to obtain a reaction solution containing a compound of formula 1;

[0011] Among them, n is taken from 0, 1; Y is selected from one of O, N and NPG, where PG is a protecting group; Alkyl represents an alkyl substituent, and [B] represents a boron functional group; The compound shown in formula 3 is a diboron reagent, and X is a halogen.

[0012] Preferably, PG is selected from Ac, Bz, Cbz, Boc.

[0013] In one or more embodiments of the present invention, in the nickel salt catalyst, the cation is Ni + , and the anion is selected from Cl – , Br – , I – , [CH3COO] – , [CF3COO] – , [acac] – and one or more of dibenzylideneacetone. Preferably, the nickel salt catalyst is NiCl.

[0014] In one or more embodiments of the present invention, the cation of the base is selected from Li + , Na + , K + and Cs + ; the anion of the base is selected from F – , CO3 2– , [CH3COO] – , [CF3COO] – , [OMe] – and [O t Bu] – . Preferably, the base is LiOMe.

[0015] In one or more embodiments of the present invention, an additive is added to the reaction system, the additive is a salt, and the cation of the salt is Li + , Na +, K + , Cs + and Mg 2+ or more than one of them; the anion of the salt is selected from F – , Cl – , Br – , I – and SO4 2– or more than one of them. Preferably, the additive is KI.

[0016] In one or more embodiments of the present invention, the diamine ligand is selected from one of the following compounds:

[0017]

[0018] wherein, R1 and R2 are each independently selected from one of H, OMe, and t-Bu; R3 is selected from one of Me and Bn.

[0019] In one or more embodiments of the present invention, Alkyl is selected from one of halogen, ester group, carbonyl group, alkoxy group, alkenyl group, aryl group, halogen-substituted aryl group, methoxy-substituted aryl group, trifluoromethyl-substituted aryl group, alkyl-substituted amino group, alkyl-substituted amide group, ether group, and cyano group.

[0020] In one or more embodiments of the present invention, the compound of formula 3 is selected from one or more of the following compounds:

[0021]

[0022] In one or more embodiments of the present invention, the reaction is carried out in a solvent; preferably, the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and acetone; more preferably, the molar volume ratio of the compound shown in formula 2 to the solvent is 1:2.

[0023] In one or more embodiments of the present invention, the structural formula of the 2-alkyl-4-boronoheterocyclic compound is as shown in formula 5 below:

[0024]

[0025] The reaction formula for stereoselectively preparing 2-alkyl-4-boronoheterocyclic compounds is as shown below:

[0026]

[0027] In one or more embodiments of the present invention, 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:(1.5 - 3.5):1.5; preferably, the molar ratio of the nickel salt catalyst, the diamine ligand, the base, the additive and the compound represented by Formula 2 is 0.05:0.05:(1.5 - 3.5):0.6:1.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0029] 1. The present invention provides a method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds, which uses an alkene, an alkyl halide and a diboron reagent, and under the action of a metal nickel catalyst, a one-pot reaction is carried out to prepare cis-2-alkyl-4-boryl heterocyclic compounds. 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 regioselectivity and stereoselectivity;

[0030] 2. The raw materials used in the method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds provided by the present invention are cheap and easily available, the operation is simple, it can be scaled up to the gram scale, and heterocyclic-2,4-alkylboronated products can be efficiently synthesized;

[0031] 3. The product synthesized by the method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds provided by the present invention contains a boron group, and the target compound can be further stereoselectively transformed to simply and efficiently synthesize other functionalized 2,4-disubstituted heterocyclic organic compounds, providing a new method for synthesizing complex drug molecules and drug lead compounds. Detailed Embodiments

[0032] The following will explain the solution of the present invention in conjunction with the embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in the field or according to the product specifications. The methods used, unless otherwise specified, are all conventional methods well-known in the art, and the consumables and reagents used, unless otherwise specified, are all commercially available. Unless otherwise stated, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the recorded content can also be applied to the present invention.

[0033] In the following examples, B2pin2 refers to bis(pinacolato)diboron; NiCl2·DME refers to nickel(II) chloride bis(ethylene glycol dimethyl ether) complex, LiOMe refers to lithium methoxide, KI refers to potassium iodide, Dioxane refers to 1,4-dioxane, and NMP refers to N-methylpyrrolidone. L represents a diamine ligand, and the diamine ligand is selected from one of the following compounds:

[0034]

[0035] Wherein, R1 and R2 are each independently selected from one of H, OMe, and t-Bu; R3 is selected from one of Me and Bn.

[0036] Specifically, L1 to L10 respectively represent the following diamine ligands:

[0037]

[0038] Example 1

[0039] The reaction formula for preparing 2-alkyl-4-boryl heterocyclic compounds is as follows:

[0040]

[0041] According to the above reaction formula, in Schemes 1 to 10 of Table 1 below, the common reaction conditions are: Compound 2a (1.0 equiv), Compound 3a (1.5 equiv), Compound 4a (1.5 equiv), NiCl2·DME (5 mol%), L (5 mol%), LiOMe (1.5 equiv), 1,4-dioxane, 50 °C, 20 h;

[0042] Condition b: Change the equivalents of Compound 3a and the base, and successively change to Compound 3a (1.4 mmol, 3.5 equiv), LiOMe (1.4 mmol, 3.5 equiv);

[0043] Condition c: Add additive KI (0.6 equiv).

[0044] The yields, dr, and ee (%) of different diamine ligands and solvents are shown in Table 1 below:

[0045] Table 1 Yields, dr, and ee (%) of different diamine ligands and solvents

[0046]

[0047]

[0048] Example 2

[0049]

[0050] In an argon-filled glove box, bis(ethylene glycol dimethyl ether)nickel(II) chloride (4.4 mg, 0.02 mmol), L4 (5.3 mg, 0.02 mmol), lithium methoxide (53.2 mg, 1.4 mmol), KI (40.0 mg, 0.24 mmol) and pinacol diboronate (355.6 mg, 1.4 mmol) were dissolved in 1 mL of dry 1,4-dioxane solvent. Then 2,5-dihydrofuran (31 μL, 0.4 mmol) and 5-(2-bromoethyl)-2,3-dihydrobenzofuran (139.0 mg, 0.6 mmol) were added. After that, another 1 mL of dry 1,4-dioxane was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was obtained by column chromatography purification.

[0051] 2-((3S,5R)-5-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)tetrahydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oily liquid, yield 74%, dr = 17:1, ee = 95%). 1 H NMR (600 MHz, Chloroform-d) δ 7.03 (d, J = 1.9 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.68 (d, J = 8.1 Hz, 1H), 4.53 (t, J = 8.6 Hz, 2H), 3.97 (t, J = 8.4 Hz, 1H), 3.83 - 3.77 (m, 2H), 3.16 (t, J = 8.6 Hz, 2H), 2.67 (ddd, J = 13.8, 10.1, 5.7 Hz, 1H), 2.58 (ddd, J = 13.8, 10.0, 6.2 Hz, 1H), 2.14 (ddd, J = 12.1, 7.8, 5.5 Hz, 1H), 1.88 (dddd, J = 13.2, 10.0, 7.3, 5.7 Hz, 1H), 1.72 (dddd, J = 25.6, 11.6, 9.8, 6.9 Hz, 2H), 1.46 (td, J = 11.7, 9.1 Hz, 1H), 1.24 (s, 12H) ppm; 13 C NMR (151 MHz, CDCl3) δ 158.2, 134.3, 127.8, 127.0, 125.0, 109.0, 83.5, 79.7, 71.2, 69.7, 37.9, 35.0, 32.3, 29.9, 24.8 ppm; 1111B NMR (128 MHz, Chloroform-d) δ 33.52 ppm; HRMS (ESI) calculated [M+H] + for C 20 H 30 BO4 + = 345.2232, found: 345.2224. [α] 20 D = +2.3 (c = 0.57, CHCl3), the corresponding alcohol after oxidation. HPLC analysis (OD-H, n-Hexane:i-Propanol = 95:5 as eluent, 1 mL / min, 220 nm) indicated 95% ee: t R (minor) = 23.0 min, t R (major) = 27.2 min, the corresponding alcohol after oxidation.

[0052] Example 3

[0053]

[0054] In an argon-filled glove box, nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L4 (5.3 mg, 0.02 mmol), lithium methoxide (53.2 mg, 1.4 mmol), KI (40.0 mg, 0.24 mmol) and bis(pinacolato)diboron (355.6 mg, 1.4 mmol) were dissolved in 1 mL of dry 1,4-dioxane solvent. Then 3,6-dihydropyran (37 μL, 0.4 mmol) and 5-(2-bromoethyl)-2,3-dihydrobenzofuran (139.0 mg, 0.6 mmol) were added. After that, another 1 mL of dry 1,4-dioxane solvent was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product was obtained by column chromatography purification

[0055] 2-((2R,4R)-2-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)tetrahydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oily liquid, yield 18%, dr > 20:1, ee = 93%). 11H NMR (400 MHz, Chloroform-d) δ 7.00 (d, J = 1.9 Hz, 1H), 6.92 - 6.87 (m, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.52 (t, J = 8.7 Hz, 2H), 4.04 - 3.97 (m, 1H), 3.44 - 3.32 (m, 1H), 3.24 - 3.10 (m, 3H), 2.66 (ddd, J = 13.8, 9.9, 5.5 Hz, 1H), 2.56 (ddd, J = 13.8, 9.7, 6.8 Hz, 1H), 1.74 (dddd, J = 13.4, 9.7, 7.7, 5.6 Hz, 2H), 1.66 - 1.59 (m, 2H), 1.57 - 1.45 (m, 2H), 1.22 (s, 12H), 1.18 - 1.09 (m, 1H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 158.2, 134.5, 127.9, 127.0, 125.0, 109.0, 83.2, 77.6, 71.2, 69.3, 38.9, 32.9, 31.2, 29.9, 27.4, 24.85, 24.83 ppm; 11 11B NMR (128 MHz, Chloroform-d) δ 33.40 ppm; HRMS (ESI) calculated [M + H] + for C 21 H 32 BO4 + = 359.2388, found: 359.2381. [α] 20 D = +6.0 (c = 0.25, CHCl3), the corresponding alcohol after oxidation. HPLC analysis (OD-H, n-Hexane:i-Propanol = 90:10 as eluent, 1 mL / min, 254 nm) indicated 93% ee: t R (minor) = 21.0 min, t R (major) = 27.1 min, the corresponding alcohol after oxidation.

[0056] Example 4

[0057]

[0058] In an argon-filled glove box, nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L4 (5.3 mg, 0.02 mmol), lithium methoxide (30.4 mg, 0.8 mmol), KI (40.0 mg, 0.24 mmol) and bis(pinacolato)diboron (203.2 mg, 0.8 mmol) were dissolved in 1 mL of dry 1,4-dioxane solvent. Then 3,6-dihydropyran (37 μL, 0.4 mmol) and benzyl chloride (71 μL, 0.6 mmol) were added. After that, another 1 mL of dry 1,4-dioxane solvent was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product 2-((2S,4R)-2-benzyltetrahydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oily liquid, yield 16%, dr > 20:1, ee = 85%) was obtained by column chromatography purification. 1 HNMR (400 MHz, Chloroform-d) δ 7.29 - 7.25 (m, 2H), 7.22 - 7.16 (m, 3H), 3.99 (dt, J = 11.3, 3.3 Hz, 1H), 3.50 - 3.33 (m, 2H), 2.84 (dd, J = 13.7, 6.7 Hz, 1H), 2.63 (dd, J = 13.8, 6.3 Hz, 1H), 1.68 - 1.65 (m, 1H), 1.56 - 1.50 (m, 2H), 1.30 - 1.27 (m, 1H), 1.21 (s, 12H), 1.17 - 1.06 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 139.0, 129.5, 128.3, 126.2, 83.2, 79.5, 69.5, 43.3, 32.5, 27.3, 24.8 ppm; 11 B NMR (128 MHz, Chloroform-d) δ 33.25 ppm; HRMS (ESI) calculated [M + H] + for C 18 H 28 BO3 + = 303.2126, found: 303.2123. [α] 20 D=-5.0 (c = 0.21 CHCl3), the corresponding alcohol after oxidation. HPLC analysis (OD-H, n-Hexane:i-Propanol = 95:5 as eluent, 1 mL / min, 220 nm) indicated 85% ee: t R (minor) = 10.3 min, t R (major) = 12.3 min, the corresponding alcohol after oxidation.

[0059] Example 5

[0060]

[0061] In an argon-filled glove box, nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then 2,5-dihydrofuran (31 μL, 0.4 mmol) and ethyl 4-bromobutyrate (86 μL, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 h. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product Cis-ethyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydrofuran-2-yl)butanoate (colorless oily liquid, yield 85%, dr = 16:1) was obtained by column chromatography purification. 1 1H NMR (600 MHz, Chloroform-d) δ 4.12 (q, J = 7.1 Hz, 2H), 3.95 (dd, J = 8.8, 8.1 Hz, 1H), 3.80 (ddt, J = 9.2, 6.8, 5.5 Hz, 1H), 3.76 (dd, J = 9.8, 8.1 Hz, 1H), 2.33 (ddd, J = 8.0, 6.9, 3.7 Hz, 2H), 2.13 (ddd, J = 12.0, 7.7, 5.5 Hz, 1H), 1.80 - 1.61 (m, 4H), 1.51 (ddt, J = 13.2, 11.0, 5.3 Hz, 1H), 1.42 (td, J = 11.8, 9.2 Hz, 1H), 1.26 - 1.23 (m, 15H). 1313C NMR (151 MHz, Chloroform-d) δ 173.8, 83.5, 80.1, 69.8, 60.4, 35.1, 35.0, 34.5, 24.9, 22.1, 14.4 ppm; 11 11B NMR (128 MHz, Chloroform-d) δ 33.51 ppm; HRMS (ESI) calculated [M+H] + for C 16 H 30 BO5 + = 313.2181, found: 313.2182.

[0062] Example 6

[0063]

[0064] In an argon-filled glove box, bis(ethylene glycol dimethyl ether)nickel(II) chloride (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then 2,5-dihydrofuran (31 μL, 0.4 mmol) and tert-butyl 4-bromopiperidine-1-carboxylate (161.7 mg, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product Cis-

[0065] tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydrofuran-2-yl)piperidine-1-carboxylate (white solid, yield 52%, dr > 20:1) was obtained by column chromatography purification. 1HNMR(400MHz,Chloroform-d)δ4.09(s,2H),3.97 - 3.92(m,1H),3.74 - 3.60(m,1H),3.54 - 3.41(m,1H),2.69 - 2.57(m,2H),2.04(ddd,J=12.5,7.5,5.5Hz,1H),1.85(dt,J=12.9,2.9Hz,1H),1.72 - 1.61(m,1H),1.58 - 1.44(m,3H),1.41(d,J=1.1Hz,9H),1.21(d,J=1.1Hz,12H),1.17 - 1.09(m,2H). 13 C NMR(101MHz,CDCl3)δ155.0,84.2,83.5,79.3,69.9,43.8,41.6,32.9,29.5,28.6,28.2,24.8ppm; 11 B NMR(128MHz,Chloroform-d)δ34.28ppm;HRMS(ESI)calculated[M+H] + for C 20 H 37 BNO5 + =382.2759,found:382.2757.

[0066] Example 7

[0067]

[0068] In an argon-filled glove box, nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then 3,6-dihydropyran (37 μL, 0.4 mmol) and 1-bromo-3-phenylpropane (93 μL, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product Cis-4,4,5,5-tetramethyl-2-(2-(3-phenylpropyl)tetrahydro-2H-pyran-4-yl)-1,3,2-dioxaborolane (colorless oily liquid, yield 71%, dr > 20:1) was obtained by column chromatography purification. 11H NMR (600 MHz, Chloroform-d) δ 7.28 - 7.23 (m, 2H), 7.18 - 7.14 (m, 3H), 3.98 (ddd, J = 11.3, 4.3, 1.8 Hz, 1H), 3.39 (td, J = 11.4, 2.9 Hz, 1H), 3.22 (dddd, J = 10.5, 7.3, 5.2, 2.1 Hz, 1H), 2.60 (t, J = 7.8 Hz, 2H), 1.79 - 1.70 (m, 1H), 1.68 - 1.60 (m, 2H), 1.56 - 1.48 (m, 3H), 1.46 - 1.39 (m, 1H), 1.23 (s, 12H), 1.18 - 1.11 (m, 1H). 13 13C NMR (151 MHz, CDCl3) δ 142.7, 128.6, 128.4, 125.7, 83.2, 78.3, 69.3, 36.4, 36.2, 33.0, 27.5, 27.4, 24.89, 24.86 ppm; 11 11B NMR (128 MHz, Chloroform-d) δ 32.64 ppm; HRMS (ESI) calculated [M + H] + for C 20 H 32 BO3 + = 331.2439, found: 331.2436.

[0069] Example 8

[0070]

[0071] In an argon-filled glove box, bis(ethylene glycol dimethyl ether)nickel(II) chloride (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then 3,6-dihydropyran (37 μL, 0.4 mmol) and benzyl chloride (71 μL, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product Cis-2-(2-benzyltetrahydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (colorless oily liquid, yield 69%, dr > 20:1) was obtained by column chromatography purification. 11H NMR (400 MHz, Chloroform-d) δ 7.29 - 7.25 (m, 2H), 7.22 - 7.16 (m, 3H), 3.99 (dt, J = 11.3, 3.3 Hz, 1H), 3.50 - 3.33 (m, 2H), 2.84 (dd, J = 13.7, 6.7 Hz, 1H), 2.63 (dd, J = 13.8, 6.3 Hz, 1H), 1.68 - 1.65 (m, 1H), 1.56 - 1.50 (m, 2H), 1.30 - 1.27 (m, 1H), 1.21 (s, 12H), 1.17 - 1.06 (m, 1H). 13 13C NMR (101 MHz, CDCl3) δ 139.0, 129.5, 128.3, 126.2, 83.2, 79.5, 69.5, 43.3, 32.5, 27.3, 24.8 ppm; 11 11B NMR (128 MHz, Chloroform-d) δ 33.25 ppm; HRMS (ESI) calculated [M+H] + for C 18 H 28 BO3 + = 303.2126, found: 303.2123.

[0072] Example 9

[0073]

[0074] In an argon-filled glove box, bis(ethylene glycol dimethyl ether)nickel(II) chloride (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then N-BOC-1,2,3,6-tetrahydropyridine (73.3 mg, 0.4 mmol) and 4-bromobutyl acrylate (61 μL, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the product Cis-tert-butyl-2-(3-cyanopropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-piperidine-1-carboxylate (white solid, yield 68%, dr > 20:1) was obtained by column chromatography purification. 1HNMR(600MHz,Chloroform-d)δ4.10(dq,J=10.2,5.3Hz,1H),3.92-3.83(m,1H),2.79(ddd,J=13.7,12.2,3.8Hz,1H),2.38(t,J=7.0Hz,2H),1.85(dt,J=13.6,6.2Hz,1H),1.81-1.69(m,2H),1.69-1.58(m,4H),1.56-1.50(m,1H),1.45(s,9H),1.26(s,12H),1.23-1.18(m,1H). 13 C NMR(151MHz,CDCl3)δ155.3,119.7,83.4,79.3,50.76,37.9,31.1,29.2,28.5,25.5,25.0,24.8,22.5,16.9ppm; 11 B NMR(128MHz,Chloroform-d)δ33.00ppm;HRMS(ESI)calculated[M+H] + for C 20 H 36 BN2O4 + =379.2763,found:379.2759.

[0075] Example 10

[0076]

[0077] In a glove box filled with argon, dissolve nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol), and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) in 1 mL of dry N-methylpyrrolidone solvent. Then add N-Boc-3-pyrroline (69.0 mg, 0.4 mmol) and 1-bromo-3-phenylpropane (93 μL, 0.6 mmol). After that, add another 1 mL of dry N-methylpyrrolidone. Seal the reaction tube and take it out of the glove box. React at 50 °C for 20 hours. After the reaction is completed, concentrate under reduced pressure to remove the reaction solvent. Then dissolve in tetrahydrofuran (2 mL), add NaOH (1.2 mL, 2 M aqueous solution, 2 mmol) and H2O2 (1.2 mL, 30% aqueous solution, 1.1 mmol), react at room temperature for 4 hours, quench with sodium thiosulfate, extract, dry, and concentrate under reduced pressure to remove the solvent. Purify by column chromatography to obtain the product Cis-tert-butyl 4-hydroxy-2-(3-phenylpropyl)pyrrolidine-1-carboxylate (white solid, yield 59%, dr > 20:1). 1 H NMR (600 MHz, Chloroform-d) δ 7.30 - 7.24 (m, 2H), 7.20 - 7.14 (m, 3H), 4.41 - 4.35 (m, 1H), 3.94 - 3.56 (m, 2H), 3.24 (ddd, J = 11.9, 3.6, 1.1 Hz, 1H), 2.74 - 2.46 (m, 2H), 2.16 (ddd, J = 13.9, 8.4, 5.9 Hz, 1H), 2.10 - 1.82 (m, 2H), 1.76 - 1.71 (m, 1H), 1.67 - 1.56 (m, 3H), 1.43 (s, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 154.7, 142.6, 128.5, 128.4, 125.8, 79.5, 71.0, 70.2, 57.0, 54.7, 39.1, 36.0, 35.0, 28.6 ppm; HRMS (ESI) calculated [M+H] + for C 18 H 28 NO3 + = 306.2064, found: 306.2057.

[0078] Example 11

[0079]

[0080] In an argon-filled glove box, nickel(II) chloride bis(ethylene glycol dimethyl ether) (4.4 mg, 0.02 mmol), L1 (6.0 mg, 0.02 mmol), lithium methoxide (22.8 mg, 0.6 mmol) and bis(pinacolato)diboron (152.4 mg, 0.6 mmol) were dissolved in 1 mL of dry N-methylpyrrolidone solvent. Then, benzyl 2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (117.3 mg, 0.4 mmol) and 1-bromo-3-phenylpropane (93 μL, 0.6 mmol) were added. After that, another 1 mL of dry N-methylpyrrolidone was added. The reaction tube was sealed and taken out of the glove box, and the reaction was carried out at 50 °C for 20 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure. The product Cis-benzyl 2-phenyl-6-(3-phenylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-1-carboxylate (colorless oily liquid, yield 46%, dr>20:1) was obtained by column chromatography purification. 1 H NMR (400 MHz, Chloroform-d) δ 7.34 - 7.21 (m, 10H), 7.20 - 7.12 (m, 5H), 5.24 (t, J = 3.9 Hz, 1H), 5.16 - 4.98 (m, 2H), 3.96 (t, J = 6.3 Hz, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.29 - 2.11 (m, 2H), 1.93 - 1.83 (m, 2H), 1.83 - 1.65 (m, 3H), 1.62 - 1.53 (m, 1H), 1.22 (d, J = 2.1 Hz, 12H), 1.15 - 1.04 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 156.4, 142.7, 137.0, 128.5, 128.41, 128.38, 128.3, 127.8, 126.4, 126.0, 125.8, 83.4, 66.9, 55.5, 52.8, 36.3, 36.1, 29.1, 28.4, 25.1, 24.9, 24.8 ppm; 11 B NMR (128 MHz, Chloroform-d) δ 35.43 ppm; HRMS (ESI) calculated [M+H] + for C 34 H 43 BNO4 += 540.3280, found: 540.3268.

[0081] In the following Examples 12 to 27, the synthesis of 2-alkyl-4-boryl heterocyclic compounds was carried out with reference to the method steps of Example 2 above. For the oxidation of 2-alkyl-4-boryl heterocyclic compounds in Examples 17 and 27, reference was made to the method steps of Example 10. Among the compounds 4Alkyl-X used in Examples 12 to 27, X was Br. The structures and names of the synthesized compounds, NMR, ee values, HRMS data and yields are shown in Table 2 below:

[0082] Table 2 Product Structures, Names, NMR, HRMS and Yields of Examples 12 to 27

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention, and all of them should be included within the protection scope of the present invention.

Claims

1. A method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds, characterized in that, The structural formula of the 2-alkyl-4-boryl heterocyclic compound is as shown in Formula 1 below: The reaction formula for the stereoselective preparation of 2-alkyl-4-boryl heterocyclic compounds is as shown below: ； A method for the stereoselective preparation of 2-alkyl-4-boryl heterocyclic compounds, comprising: reacting a compound of Formula 2, a compound of Formula 3 and a compound of Formula 4 under the action of a nickel salt catalyst, a diamine ligand and a base to obtain a reaction solution containing the compound of Formula 1; Among them, the compound of formula 2 is selected from , , , the compound of formula 3 is B2pin2, and the structure is , the compound of formula 4 is selected from , , , , , ; the compound of formula 1 is selected from , , , , , , , , ; The nickel salt catalyst is NiCl2·DME; The cation of the base is Li + , and the anion of the base is [OMe] – ; The diamine ligand is selected from one of the following compounds: wherein R1 is H; The reaction is carried out in a solvent selected from one or more of tetrahydrofuran, 1,4-dioxane, and N-methylpyrrolidone.

2. The method for stereoselectively preparing 2-alkyl-4-boronoheterocyclic compounds according to claim 1, wherein An additive is added to the reaction system, the additive is a salt, and the cation of the salt is K + ; the anion of the salt is I – .

3. The method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds according to claim 1, wherein The molar volume ratio of the compound shown in Formula 2 to the solvent is 1:

2.

4. The method for stereoselectively preparing 2-alkyl-4-boryl heterocyclic compounds according to claim 1, wherein The molar ratio of the compound shown in Formula 2, the compound shown in Formula 3 and the compound shown in Formula 4 is 1: (1.5 - 3.5): 1.

5.

5. The method for stereoselectively preparing 2-alkyl-4-boronoheterocyclic compounds according to claim 2, wherein The molar ratio of the nickel salt catalyst, the diamine ligand, the base, the additive to the compound shown in Formula 2 is 0.05:0.05: (1.5 - 3.5):0.6:1.

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