A bicyclo[3,1,0]hexane organic borane compound and preparation method thereof

Abstract

The invention provides a bicyclo[3,1,0]hexane organoborane compound and a preparation method thereof, wherein the compound is prepared by using 1,6-ene yne compounds and borane complexes as raw materials, and synthesizing a novel skeleton organoborane compound by a one-step reaction under the action of a gold catalyst and a silver salt. Not only is the bicyclo[3,1,0]hexane structure an important skeleton of natural product pharmaceutical chemistry, but the organoboron unit can also be used as an important platform intermediate for various derivatizations to prepare a variety of functional compounds, and such compounds have important potential for new drug research and development. The preparation method of the present invention has convenient and easy-to-obtain raw materials, simple operating steps, and mild reaction conditions. It is a unique method for preparing bicyclo[3,1,0]hexane organoborane compounds, and is suitable for the needs of large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a bicyclo[3,1,0]hexane organic borane compound and a preparation method thereof. Background Art

[0002] Bicyclo[3,1,0]hexane is a ubiquitous biologically active structural unit in natural products and drug molecules. This bicyclic structural unit has strong tension and is an important intermediate in ring-opening reactions. On the other hand, organoboron compounds are not only indispensable platform molecules in synthetic chemistry, but also boron-containing units are becoming important pharmacophores in drug discovery and are attracting much attention. Therefore, the introduction of boron units into the bicyclo[3,1,0]hexane skeleton to synthesize bicyclo[3,1,0]hexane organoboron compounds will help discover new drug molecules.

[0003] Recently, the research group of Jianwei Sun from the Hong Kong University of Science and Technology reported a method for the ruthenium-catalyzed synthesis of bicyclo[3,1,0]hexane organic boronate (Angew.Chem.Int.Ed.2022,61,e202204319). This method uses HBpin as the borylation raw material to synthesize a series of alkyl borate compounds. It is known that some alkyl borate compounds are easily decomposed in silica gel columns, making subsequent separation difficult, and the boron units of such borylation products cannot be diversified into new organic boron units, so there are certain limitations. Summary of the invention

[0004] The purpose of the present invention is to provide a bicyclo[3,1,0]hexane organoborane compound and a preparation method thereof, so as to overcome the defects of the prior art. The present invention uses cheap and readily available 1,6-enyne as a carbene precursor and a tetracoordinate borane as a borylation reagent. Under the catalysis of a gold catalyst, a class of bicyclo[3,1,0]hexane organoborane compounds can be quickly synthesized through a carbene borohydrogen bond insertion pathway.

[0005] In order to achieve the above object, the present invention adopts the following technical scheme:

[0006] A bicyclo[3,1,0]hexane organoborane compound, wherein the structural formula of the bicyclo[3,1,0]hexane organoborane compound is as shown in formula (1):

[0007]

[0008] Wherein, Z is C(CO2Me)2, (AcOCH2)2C, NTs, (MeOCH2)2C or PhBO2(CH2)2C; LB is NMe3, NMe(C2H8) or PPhMe2; R 1 is H, Me or Ph; R 2 It is H or Me.

[0009] A method for preparing a bicyclo[3,1,0]hexane organoborane compound, comprising: using a 1,6-enyne compound as shown in formula (2) and a borane complex as shown in formula (3), in the presence of a carbene gold catalyst as shown in formula (4) and silver hexafluorophosphate as shown in formula (5), to synthesize a bicyclo[3,1,0]hexane organoborane compound as shown in formula (1) through a one-step reaction;

[0010]

[0011] Furthermore, the specific steps include: at room temperature and air conditions, adding a carbene gold catalyst, silver hexafluorophosphate and a reaction solvent in a reaction container in sequence, and stirring evenly; then adding a borane complex and a 1,6-eneyne compound in sequence to react; finally, directly separating by silica gel column chromatography to obtain a bicyclo[3,1,0]hexane organic borane compound.

[0012] Furthermore, the molar ratio of the 1,6-enyne compound, the borane complex, the carbene gold catalyst and the silver hexafluorophosphate is 1:4:0.1:0.1.

[0013] Furthermore, the reaction solvent is dichloromethane, and 0.1 to 0.5 mmol of 1,6-enyne compound is added to every 1.0 mL of the reaction solvent.

[0014] Furthermore, the reaction time is 8-20 hours.

[0015] Furthermore, after the reaction is completed, silica gel column chromatography is directly performed for separation.

[0016] Furthermore, when separating by silica gel column chromatography, the eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 2:1 to 4:1.

[0017] Compared with the prior art, the present invention has the following beneficial technical effects:

[0018] The compound synthesized by the present invention is a novel skeleton organic borane compound containing a bicyclo[3,1,0]hexane structure. Not only is the bicyclo[3,1,0]hexane structure an important skeleton in natural product medicinal chemistry, but organic borane can also be used as an important platform molecular intermediate for various derivatizations, providing an important platform for new drug research and development. The present invention has the characteristics of convenient and easy-to-obtain raw materials, simple operation steps, mild reaction conditions, etc. It is a new method for preparing novel skeleton organic boron compounds, which is suitable for the needs of large-scale industrial production. In addition, the obtained organic borane compound can be smoothly modularized and diversified to prepare potential pharmaceutically active molecules, providing an important idea for the development of new drug molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The synthesis diagram of bicyclo[3,1,0]hexane organoborane compound;

[0020] Figure 2 This is a diagram of the diverse transformations of bicyclo[3,1,0]hexane organoborane compounds. DETAILED DESCRIPTION

[0021] The present invention is described in further detail below:

[0022] A bicyclo[3,1,0]hexane organoborane compound, such as formula (1), has the following structural formula:

[0023]

[0024] A method for preparing a bicyclo[3,1,0]hexane organoborane compound, such as Figure 1 As shown, the specific preparation scheme is as follows: using the 1,6-ene yne compound shown in formula (2) and the borane complex shown in formula (3) as starting materials, under the action of the carbene gold catalyst shown in formula (4) and the silver hexafluorophosphate shown in formula (5), a bicyclo[3,1,0]hexane organic borane compound shown in formula (1) is synthesized in one step, and the corresponding structural formula is as follows:

[0025]

[0026] A method for preparing a bicyclo[3,1,0]hexane organic borane compound, specifically comprising:

[0027] At room temperature and air, a carbene gold catalyst, silver hexafluorophosphate and a reaction solvent are added to a reaction container in sequence and stirred evenly; then a borane complex and a 1,6-enyne compound are added in sequence to react; finally, the mixture is directly separated by silica gel column chromatography, and when separated by silica gel column chromatography, an eluent is petroleum ether:ethyl acetate=2:1-4:1 (volume ratio) to obtain a bicyclo[3,1,0]hexane organic borane compound, wherein the molar ratio of the 1,6-enyne compound, the borane complex, the carbene gold catalyst and the silver hexafluorophosphate is 1:4:0.1:0.1, the reaction solvent is dichloromethane, and 0.1-0.5 mmol of the 1,6-enyne compound is added to every 1.0 mL of the reaction solvent, and the reaction time is 8-20 hours.

[0028] The specific equation is as follows:

[0029]

[0030] The present invention is described in detail below in conjunction with the embodiments and drawings to facilitate a more comprehensive understanding of the present invention by those skilled in the art, but the present invention is not limited to the scope of all embodiments. All other embodiments obtained without creative work are within the scope of protection of the present invention.

[0031] Example 1

[0032] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1aa, the reaction equation is as follows:

[0033]

[0034] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1aa, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2a (57.2 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 8 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1aa (54.5 mg, yield 76%) was obtained. After NMR analysis, the NMR data: 1 HNMRδ(500MHz, CDCl3)δ7.22-7.15(m,2H),7.14-7.09(m,2H),7.09-7.03(m,6H),3.73(s,3H),3.70(s,3H),2. 77-2.54(m,4H),2.28(s,9H),1.63-1.61(m,1H),1.58(t,J=4.3Hz,1H),0.59-0.49(m,1H),0.30-0.20(m,1H); 13 C NMR (126MHz,CDCl3)δ174.0,137.3,140.9,128.9,127.4,124.8,60.4,52.9,52.8,51.8,43.6,38.7,37.8,32.9,29.8. High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 22 H 30 BNNaO4,M+Na] +:382.2160, found:382.2153. Infrared absorption data: IR(film):ν(cm -1 )3035,2958,2896,2335,1728,1606,1521,1434,1243,1083,1064,847,736,706.

[0035] Example 2

[0036] A method for preparing a bicyclo[3,1,0]hexane organic borane compound 1ba, the reaction equation is as follows:

[0037]

[0038] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ba, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2b (60.0 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ba (51.2 mg, yield 68%) was obtained. After NMR analysis, the NMR data: 1 HNMR (500MHz, CDCl3): δ7.09 (d, J = 7.7Hz, 1H), 7.06-6.97 (m, 2H), 6.93 (d, J = 7. 3Hz,1H),3.72(s,3H),3.70(s,3H),2.79(d,J=14.1Hz,1H),2.73(dd,J=13.5Hz ,J=4.9Hz,1H),2.60(d,J=13.6Hz,1H),2.57(d,J=13.9Hz,1H),2.32(s,1H),2. 26(s,9H),1.65(t,J=4.6Hz,1H),1.51(d,J=4.1Hz,1H),0.24(t,J=5.9Hz,2H). 13C NMR (125MHz, CDCl3): δ173.9,173.3,139.2,138.7,129.2,126.9,124.9,124.9,60.7,52.8,52.7,51.7,42.8,37.9,37.8,30.7,28.3,20.3,15.4. 11 B NMR (160MHz,CDCl3):δ-2.9(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 21 H 32 BNNaO4,M+Na] + :396.2316, found:396.2310. Infrared absorption data: IR (film): ν (cm-1) 3033, 2951, 2895, 2338, 1722, 1483, 1238, 1196, 1164, 1121, 1095, 1077, 1057, 1032, 843, 750, 733.

[0039] Example 3

[0040] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ca, the reaction equation is as follows:

[0041] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ca, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2c (72.4 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 3:1), and the organic borane compound 1ca (43.2 mg, yield 50%) was obtained. After NMR analysis, the NMR data is as follows: 1HNMR (500MHz, CDCl3): δ7.56(d,J=7.4Hz,2H),7.45(d,J=8.7Hz,2H),7.40(t,J=7.6Hz,2H ),7.31-7.27(m,2H),7.19(d,J=7.9Hz,2H),3.74(s,3H),3.70(s,3H),2.74(d,J=14.1Hz, 1H),2.70(dd,J=12.8,4.9,Hz,1H),2.64(d,J=13.3Hz,1H),2.60(d,J=14.1Hz,1H),2.29( s,9H),1.66(d,J=4.5Hz,1H),1.63(d,J=4.5Hz,1H),0.61-0.57(m,1H),0.33-0.26(m,1H). 13 C NMR (125MHz, CDCl3): δ174.0,173.3,141.3,140.2,137.4,129.2,128.8,126.8,126.0,60.3,52.9,52.8,51.7,38.9,37.7,32.6,30.1,15.7. 11 BNMR (160MHz,CDCl3):δ-3.22(bs).HRMS(ESI,m / z)Calculated for[C 26 H 34 BNNaO4,M+Na] + :458.2473, found:458.2465. Infrared absorption data: IR(film):ν(cm -1 )3019,2951,2320,1728,1246,1183,1164,1083,1066,937,867,839,749,693.

[0042] Example 4

[0043] A method for preparing a bicyclo[3,1,0]hexane organic borane compound 1da, the reaction equation is as follows:

[0044]

[0045] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1da, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. iPrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2d (60.0 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1da (47.5 mg, yield 63%) was obtained. After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ7.08(t,J=7.6Hz,1H),6.95(s,1H),6.88(d,J=16.0Hz,2H),3.72(s,3H),3.69(s,3H),2.72(d,J=14.0Hz,1H),2.68(dd,J=1 3.7,5.0Hz,1H),2.62-2.55(m,2H),2.29(s,9H),2.27(s,3H),1.59(d,J= 13.0Hz,1H),1.55(t,J=4.3Hz,1H),0.59-0.51(m,1H),0.31-0.25(m,1H). 13 C NMR (125MHz, CDCl3): δ174.0,173.3,140.7,136.7,129.9,127.3,125.7,125.5,60.3,52.8,52.7,51.7,43.6,38.5,37.7,32.8,29.8,21.5,15.5. 11 BNMR (160MHz,CDCl3):δ-3.1(bs).HRMS(ESI,m / z)Calculated for[C 21 H 32 BNNaO4,M+Na] + :396.2316, found:396.2310. Infrared absorption data: IR (film): ν (cm -1 )3017,2996,2949,2326,1729,1605,1433,1241,1196,1169,1081,991,840,731.

[0046] Example 5

[0047] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ea, the reaction equation is as follows:

[0048]

[0049] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ea, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2e (67.2 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ea (49.2 mg, yield 60%) was obtained. After NMR analysis, the NMR data: 1 HNMR (500MHz, CDCl3): δ8.22(d,J=8.3Hz,1H),7.77(d,J=7.96Hz,1H),7.61(d,J=8.6Hz,1H),7.51(t, J=7.3Hz,1H),7.44(t,J=7.4Hz,1H),7.33(t,J=7.6Hz,1H),7.17(d,J=7.2Hz,1H),3.74(s,3H),3.72( s,3H),2.96(d,J=14.5Hz,1H),2.86(dd,J=13.5,5.2Hz,1H),2.69(d,J=7.9Hz,1H),2.66(d,J=8.6Hz, 1H), 2.13 (s, 9H), 2.01 (d, J = 4.2Hz, 1H), 1.79 (t, J = 4.6Hz, 1H), 0.29-0.19 (m, 1H), 0.15-0.06 (m, 1H). 13 C NMR (125MHz, CDCl3): δ174.2,173.2,137.6,134.2,133.5,127.9,126.0,125.7, 125.5,125.4,124.8,60.7,52.9,52.8,51.6,42.4,38.3,37.8,30.2,28.3,15.4. 11 B NMR (160MHz,CDCl3):δ-2.8(bs).High resolution data:HRMS(ESI,m / z)Calculated for[C 24 H 32 BNNaO4,M+Na] +:432.2316,found:432.2309.Infrared data: IR(film):ν(cm -1 )3042,3014,2996,2949,2327,1728,1594,1242,1196,1167,1082,1066,840,801,780,730.

[0050] Example 6

[0051] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1fa, the reaction equation is as follows:

[0052]

[0053] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1fa, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (1 mL) were stirred for 5 minutes; then, trimethylamine borane complex IIIA (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2f (47.6 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; the organic borane compound 1fa (30.2 mg, yield 51%) was obtained by direct silica gel column chromatography separation (according to the volume ratio, petroleum ether: ethyl acetate = 4:1). After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ3.70(s,3H),3.63(s,3H),2.56-2.53(m,1H),2.51(s,9H),2.44(d,J=14.8Hz,1H),2.17(d,J=14.8Hz,1 H),1.98(dd,J=15.1,2.5Hz,1H),1.07(s,3H),0.94(s,3H),0.90-0.85(m,1H),0.72(dd,J=7.2,2.3Hz,1H),0.46-0.41(m,1H). 13 C NMR (125MHz, CDCl3): δ174.3,172.3,67.6,52.6,52.3,51.9,41.1,39.9,36.4,34.8,26.5,23.5,21.6,17.4. 11B NMR (160MHz,CDCl3):δ-3.3(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 16 H 30 BNNaO4,M+Na] + :334.2160, found:334.2157. Infrared absorption data: IR (film): ν (cm -1 )2996,2948,2318,2264,1729,1434,1247,1169,1139,1073,995,839.

[0054] Example 7

[0055] A method for preparing a bicyclo[3,1,0]hexane organic borane compound 1ga, the reaction equation is as follows:

[0056]

[0057] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ga, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2g (42.0 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ga (10.2 mg, yield 22%) was obtained. After NMR analysis, the NMR data is as follows: 1 HNMR (500MHz, CDCl3): δ3.67(s,3H),3.65(s,3H),2.60(d,J=13.6Hz,1H),2.55(s,1H),2.53(s,9H),2.50(s,1H),2.55(dd,J =13.6,4.6Hz,1H),2.34(d,J=13.8Hz,1H),1.03-0.98(m,1H),0.85-0.78(m,1H),0.54-0.47(m,1H),0.33(d,J=13.3Hz,1H). 13C NMR (125MHz, CDCl3): δ174.0,173.3,59.9,52.8,52.6,52.1,42.7,37.0,29.1,23.7,22.8,15.6. 11 B NMR (160MHz,CDCl3):δ-3.0(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 14 H 26 BNNaO4,M+Na] + :306.1847, found:306.1843. Infrared absorption data: IR(film):ν(cm -1 )3002,2954,2317,1723,1245,1200,1183,1169,1135,1093,843.

[0058] Example 8

[0059] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ha, the reaction equation is as follows:

[0060]

[0061] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ha, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2h (62.8 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ha (47.2 mg, yield 57%) was obtained. After NMR analysis, the NMR data are as follows: 1HNMR (500MHz, CDCl3): δ7.18(t,J=7.5Hz,2H),7.11(d,J=7.7Hz,2H),7.05(t,J=7.2Hz,1H),4.02(q,J=15.4Hz,2H),3.9(s,2H),2.20(s,9H),2. 05(s,3H),1.98(d,J=14.2Hz,1H),1.75(d,J=14.2Hz,1H),1.69(d,J=3. 9Hz,1H),1.60(d,J=14.1Hz,1H),0.56-0.48(m,1H),0.22-0.15(m,1H). 13 C NMR (125MHz, CDCl3): δ171.5,171.3,141.0,128.5,127.3,124.6,68.3,68.2,51.6,49.7,43.8,40.9,37.3,31.0,21.1,21.0,16.6. 11 BNMR (160MHz,CDCl3):δ-3.8(bs).HRMS(ESI,m / z)Calculated for[C 22 H 34 BNNaO4,M+Na] + :410.2473,found:410.2465.Infrared absorption data: IR(film):ν(cm -1 )3019,2995,2941,2324,2324,2267,1734,1377,1363,1224,1182,1140,1029,989,839,699.

[0062] Example 9

[0063] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 2ia, the reaction equation is as follows:

[0064]

[0065] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ia, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. iPrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2i (51.6 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ia (40.2 mg, yield 60%) was obtained. After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ7.18(t,J=7.5Hz,2H),7.11(d,J=7.2Hz,2H),7.04(t,J =7.2Hz,1H),3.37(s,3H),3.32(s,3H),3.27(q,J=11.3Hz,2H),3.23(s,2H),2.2 6(s,9H),2.00-1.92(m,2H),1.72(d,J=13.9Hz,1H),1.67(d,J=4.0Hz,1H),1.59 (d,J=13.8Hz,1H),1.54(t,J=4.8Hz,1H),0.53-0.45(m,1H),0.29-0.21(m,1H). 13 C NMR (125MHz, CDCl3): δ141.5,128.4,127.5,124.4,78.0,77.7,59.3,59.2,51.7,51.3,44.1,41.1,40.2,37.6,31.6,16.5. 11 B NMR (160MHz,CDCl3):δ-3.6(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 20 H 34 BNNaO2,M+Na] + :354.2575, found:354.2567. Infrared absorption data: IR (film): ν (cm -1 )3018,2992,2868,2324,2265,1599,1458,1197,1180,1140,1096,989,838.

[0066] Example 10

[0067] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ja, the reaction equation is as follows:

[0068]

[0069] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ja, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2j (63.2 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ja (54.2 mg, yield 65%) was obtained. After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ7.79(d,J=7.2Hz,2H),7.41(t,J=7.3Hz,1H),7.35(t,J=7.3Hz,2H ),7.22(t,J=7.8Hz,2H),7.14(d,J=7.4Hz,2H),7.09(t,J=7.1Hz,1H),3.95-3.86(m,4H), 2.28(s,9H),2.09(dd,J=13.9,5.8Hz,1H),2.02(d,J=13.9Hz,1H),1.85(d,J=13.9Hz,1H) ,1.75(d,J=13.6Hz,1H),1.69(d,J=3.7Hz,1H),1.64(d,J=3.7Hz,1H),0.58-0.44(m,1H). 13 C NMR (125MHz, CDCl3): δ141.5,133.9,130.6,128.5,127.7,127.4,124.7,72.7,72.5,51.7,46.4,44.1,40.6,39.5,37.9,16.1. 11 B NMR (160MHz,CDCl3):δ27.1(bs),-3.8(bs). High resolution mass data: HRMS (ESI,m / z) Calculated for [C 24 H 33 B2NNaO2,M+Na] + :412.2589,found:412.2581.Infrared absorption data: IR(film):ν(cm -1)3750,3648,3566,2915,2323,1473,1456,1339,1307,1248,1140,1092,840,697,645.

[0070] Embodiment 11

[0071] A method for preparing a bicyclo[3,1,0]hexane organic borane compound 1ka, the reaction equation is as follows:

[0072]

[0073] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ka, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (0.4 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3a (73.0 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2k (55.4 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 10 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 2:1), and the organic borane compound 1ka (50.2 mg, yield 75%) was obtained. After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ7.69(d,J=8.1Hz,2H),7.26(d,J=7.8Hz,2H),3.42(q,J=9.4Hz,1H),3.35-3.18(m,3H),2 .47(s,9H),2.40(s,3H),1.02(s,3H),0.81(s,3H),0.72(d,J=5.3Hz,1H),0.70-0.62(m,1H),0.49-0.37(m,1H). 13 C NMR (125MHz, CDCl3): δ142.7,135.2,129.4,54.3,51.9,48.7,36.2,32.8,23.3,22.7,21.6,18.2,14.8. 11 B NMR (160MHz,CDCl3):δ-3.7(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 18 H 31 BN2NaO2S,M+Na] +:373.2091, found:373.2083. Infrared absorption data: IR (film): ν (cm -1 )3839,3648,2933,2866,2318,2269,1770,1331,1162,1145,1122,1096,1052,815,670,599,547,520.

[0074] Example 12

[0075] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ab, the reaction equation is as follows:

[0076]

[0077] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ab, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (2 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3b (79.2 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2a (57.2 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 20 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ab (50.5 mg, yield 66%) was obtained. After NMR analysis, the NMR data are as follows: 1 HNMR (500MHz, CDCl3): δ7.16(t,J=7.5Hz,2H),7.10(d,J=7.5Hz,2H),7.04(t, J=7.1Hz,1H),3.71(s,3H),3.67(s,3H),2.95-2.90(m,1H),2.79-2.52(m,6H) ,2.51-2.40(m,2H),2.21(s,3H),1.92-1.85(m,1H),1.78-1.73(m,2H),1.60( d,J=3.9Hz,1H),1.56(t,J=4.1Hz,1H),0.30-0.14(m,1H),0.28-0.19(m,1H). 13C NMR (125MHz, CDCl3): δ172.9,172.2,139.8,127.7,126.3,123.6,60.1,59.6, 59.3,51.8,51.6,46.9,42.6,37.9,36.6,31.8,28.8,21.6(d,J=2.8Hz),14.9. 11 B NMR (160MHz,CDCl3):δ-5.6(bs). High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 22 H 32 BNNaO4,M+Na] + :408.2316,found:408.2310.Infrared absorption data: IR(film):ν(cm -1 )3648,3566,3024,2994,2951,2310,1729,1242,1195,1167,1081,1065,864,730,699.

[0078] Example 13

[0079] A method for preparing a bicyclo[3,1,0]hexane organoborane compound 1ac, the reaction equation is as follows:

[0080]

[0081]

[0082] A method for preparing a bicyclo[3,1,0]hexane organoboron compound 1ac, the implementation scheme is as follows: under room temperature and air conditions, a dried stirring bar, a carbene gold catalyst are successively added into a reaction container. i PrAuCl (12.5 mg, 0.02 mmol, 0.1 eq), silver salt AgPF6 (10.0 mg, 0.02 mmol, 0.1 eq) and dichloromethane DCM (0.4 mL) were stirred for 5 minutes; then, trimethylamine borane complex 3c (79.2 mg, 0.08 mmol, 4.0 eq) and 1,6-ene yne compound 2a (57.2 mg, 0.2 mmol, 1.0 eq) were added in sequence, and the reaction lasted for 20 hours; directly separated by silica gel column chromatography (according to the volume ratio, petroleum ether: ethyl acetate = 4:1), and the organic borane compound 1ac (70.2 mg, yield 80%) was obtained. After NMR analysis, the NMR data is as follows: 1HNMR (500MHz, CDCl3): δ7.48-7.39(m,3H),7.38-7.32(m,2H),7.17(t,J=7. 5Hz,2H),7.11-7.04(m,3H),3.73(s,3H),3.70(s,3H),2.81(d,J=14.1Hz,1 H),2.71-2.61(m,3H),1.66(d,J=4.0Hz,1H),1.53(t,J=4.1Hz,1H),1.30(d ,J=9.8Hz,3H),1.25(d,J=9.8Hz,3H),0.60-0.48(m,1H),0.36-0.24(m,1H). 13 C NMR (125MHz, CDCl3): δ174.0,173.3,140.6,131.1,131.0,130.6,130.2,128.9(d,J=1.6Hz),128.8,12 7.4,124.8,60.2,52.9,52.8,43.4,40.7,40.5,37.9,33.2,30.0,12.2,11.0,10.7(d,J=3.6Hz),10.4. 11 B NMR (160MHz, CDCl3): δ-29.0 (bs). 31 P NMR (200MHz,CDCl3):δ-0.37. High resolution mass spectrometry data: HRMS (ESI,m / z) Calculated for [C 25 H 32 BNaO4P,M+Na] + :461.2023,found:461.2016.Infrared absorption data: IR(film):ν(cm -1 )3839,3648,3566,3024,2952,2313,2248,1725,1241,1196,1166,1080,950,921,747,699,687.

[0083] The bicyclo[3,1,0]hexane organoborane compound obtained by the present invention can be used to construct a variety of products, which provide an important platform for drug screening and further synthetic transformation. Figure 2 As shown, 1aa can be efficiently converted into various compounds such as 6, 7, 8, 9, 10, and 11.

[0084]

[0085] (1) pinacol, THF, 70℃; (2) neopentyl glycol, THF, 70℃ (3) 1,8-diaminonaphthalene, THF, 70℃; (4) N-methylimidodiacetic acid, toluene / DMSO=5:1, 70℃; (5) NCS, DCM, 0℃, (6) H2O2, MeOH, 60℃.

[0086] The specific conversion process is as follows:

[0087] (1) At 70°C, 1aa and pinacol were fully reacted in tetrahydrofuran solution, and after the reaction was complete, column chromatography was performed to separate 6 with a yield of 90%; (2) At 70°C, 1aa and neopentyl glycol were fully reacted in tetrahydrofuran solution, and after the reaction was complete, column chromatography was performed to separate 7 with a yield of 87%; (3) At 70°C, 1aa and 1,8-diaminonaphthalene were fully reacted in tetrahydrofuran solution, and after the reaction was complete, column chromatography was performed to separate 8 with a yield of 86%; (4) 7 At 0°C, 1aa and N-methyliminodiacetic acid were reacted in a mixed solvent of toluene and dimethyl sulfoxide. After the reaction was completed, the mixture was separated by column chromatography to obtain 9 in a yield of 78%; (5) 1aa and N-chlorosuccinimide were reacted in dichloromethane at 0°C. After the reaction was completed, the mixture was separated by column chromatography to obtain compound 10 in a yield of 80%; (6) 1aa and hydrogen peroxide were reacted in methanol at 60°C. After the reaction was completed, the mixture was separated by column chromatography to obtain 11 in a yield of 89%.

[0088] The embodiments described above are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The embodiments and features in the embodiments of the present application can be arbitrarily combined with each other without conflict. The protection scope of the present invention shall be the technical solutions recorded in the claims, including equivalent replacement solutions of the technical features in the technical solutions recorded in the claims. That is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.

Claims

1. A method for preparing a bicyclo[3,1,0]hexane organoborane compound, wherein the bicyclo[3,1,0]hexane organoborane compound has a structural formula as shown in formula (1): in, Z is C(CO2Me)2, (AcOCH2)2C, NTs, (MeOCH2)2C or LB is NMe3, or PPhMe2;R 1 is H, Me or Ph; R 2 is H or Me; The method is characterized in that a bicyclo[3,1,0]hexane organic borane compound as shown in formula (1) is synthesized by a one-step reaction using a 1,6-enyne compound as shown in formula (2) and a borane complex as shown in formula (3) in the presence of a carbene gold catalyst as shown in formula (4) and silver hexafluorophosphate as shown in formula (5); 2. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 1, characterized in that: The specific steps include: at room temperature and air conditions, adding a carbene gold catalyst, silver hexafluorophosphate and a reaction solvent in a reaction container in sequence and stirring them evenly; then adding a borane complex and a 1,6-eneyne compound in sequence to react; finally, directly separating by silica gel column chromatography to obtain a bicyclo[3,1,0]hexane organic borane compound.

3. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 2, characterized in that: The molar ratio of the 1,6-eneyne compound, the borane complex, the carbene gold catalyst and the silver hexafluorophosphate is 1:4:0.1:0.

1.

4. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 2, characterized in that: The reaction solvent is dichloromethane, and 0.1-0.5 mmol of 1,6-enyne compound is added to every 1.0 mL of the reaction solvent.

5. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 2, characterized in that: The reaction time is 8-20 hours.

6. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 2, characterized in that: After the reaction is completed, silica gel column chromatography is directly performed for separation.

7. The method for preparing a bicyclo[3,1,0]hexane organoborane compound according to claim 2, characterized in that: When separating by silica gel column chromatography, the eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 2:1 to 4:1.

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