BNC-1, 3-dipole and synthetic method and application thereof

Abstract

The invention relates to a BNC-1, 3-dipole as well as a synthesis method and application thereof. The preparation method comprises the following steps: dissolving a precursor compound boron aminobromide 1 in a mixed solvent of tetrahydrofuran and hexane, slowly dropwise adding an alkali mixed solution at a low temperature of-78 DEG C, gradually heating to room temperature, filtering, precipitating and draining the solvent; and washing the obtained viscous solid with cold pentane twice, and then pumping out the solvent to obtain the BNC-1, 3-dipole. The bora-1, 3-dipole synthesis method is used for synthesis of bora-1, 3-dipole through the process of simultaneously pulling out hydrogen bromide and hydrogen in one step, and is simple and high in yield. The prepared BNC-1, 3-dipole can be subjected to [3 + 1], [3 + 2] and [3 + 3] cycloaddition reaction with a dipole affinity, and is used for synthesizing a 4-6-membered heterocyclic compound.

Description

Technical Field

[0001] This invention belongs to the field of boron organic chemistry technology, and relates to BNC-1,3-dipoles containing amphiphilic boron and their synthesis methods. Background Technology

[0002] The 1,3-dipolar cycloaddition reaction refers to the reaction in which a 1,3-dipolar atom reacts with a dipolarophile (alkene, alkyne, carbonyl group, imine, etc.) to form a five-membered heterocycle, as shown in the following equation:

[0003]

[0004] This transformation is stereospecific and meets 100% atom economy, representing the most efficient synthetic strategy for five-membered heterocycles to date. Since Huisgen first proposed the concept of 1,3-dipolar cycloaddition (1,3-DC) in the 1960s, 1,3-dipolar cycloaddition reactions have shown important applications in organic synthesis, biomedicine, materials science, and life sciences.

[0005] 1,3-Dipoles are delocalized systems with three centers and four electrons. Based on the structure of the central atom, they are generally classified into propargyl / allene and allyl types. Introducing heteroatoms into the 4π framework of 1,3-dipoles effectively alters the energy and composition of π bonds and frontier orbitals, thus effectively modulating their reactivity. Over the past few decades, a series of transient or stable 1,3-dipoles containing carbon, nitrogen, oxygen, sulfur, and phosphorus, and their cyclization reactions have been reported. However, borohydride-1,3-dipole analogs are rarely reported. To date, only... The specific structures of BNP-1,3-dipole A reported by our research group in 1993, BNN-1,3-dipole B and C reported by Kong Lingbing's research group in 2020 and Cummins and Gilliard in 2024, respectively, are as follows:

[0006]

[0007] These boro-1,3-dipoles can react with a series of polar or nonpolar dipeptides to generate structurally diverse organoboron derivatives. Of particular note is that the transient BNN-1,3-dipol B can even complete the dearomatization 1,3-dipolar cycloaddition reaction with a neighboring aromatic ring at room temperature, thus opening up new possibilities for the dearomatization functionalization of aromatics. Therefore, the development of novel boro-1,3-dipoles is of great significance both in terms of basic research and practical applications. Summary of the Invention

[0008] In view of the current research status, especially the limited number of reports on boro-1,3-dipoles and the limited range of elements involved, this invention provides a BNC-1,3-dipol, its synthesis method, and its applications. Under strongly alkaline conditions, this invention enables a one-step, highly efficient process for removing hydrogen bromide and abstracting hydrogen from bromide precursors, resulting in a simple and efficient BNC-1,3-dipol. This boro-1,3-dipol can undergo [3+1], [3+2], and [3+3] dipolar cycloaddition reactions with dipolarophiles, and can be used to prepare 4-6 membered heterocyclic compounds.

[0009] The technical solution of this invention can be summarized as follows:

[0010] A BNC-1,3-dipole has the structure shown in Formula I:

[0011]

[0012] In Formula I, R1 is a sterically hindered aryl or alkyl group, and R2 and R3 are selected from alkyl or aryl groups. R2 and R3 may be the same or different.

[0013] According to the present invention, preferably, R1 is selected from 2,6-diphenylphenyl (Dpp), 2,6-bis(2,4,6-trimethylphenyl)phenyl (Dmp), or 2,4,6-tritert-butylphenyl (Mes) * R2 and R3 are fluorene groups.

[0014] According to the present invention, the method for synthesizing the BNC-1,3-dipole includes the following steps:

[0015]

[0016] Under a nitrogen atmosphere, precursor compound 1 was added to a solvent, and a base was added at low temperature. The temperature was then increased to react, and the solid was obtained by filtration and purification to obtain the target BNC-1,3-dipole 2.

[0017] The precursor compound 1 has the structure shown in Formula II:

[0018]

[0019] The meanings of R1, R2, and R3 in Equation II are the same as those in Equation I.

[0020] According to the present invention, preferably, the solvent is a mixture of tetrahydrofuran (THF) and hexane (Hex); more preferably, the volume ratio of the mixed solvent is v(THF):v(Hex) = 1:5.

[0021] According to the present invention, preferably, the low temperature condition is between -78°C and 0°C.

[0022] According to the present invention, preferably, the alkali is lithium diisopropylamino (LDA), lithium hexamethyldisilamide (LiHMDS), and n-butyllithium, which can remove hydrogen bromide and hydrogen on carbon atoms in the molecular structure; most preferably, LDA.

[0023] According to the present invention, preferably, the molar ratio of precursor compound 1 to base is 1:2.

[0024] According to the present invention, preferably, the reaction temperature is 20°C.

[0025] According to the present invention, preferably, the purification process is as follows: the filtered solid is washed with pentane solvent and then the solvent is removed.

[0026] According to the present invention, the use of the above-mentioned amphiphilic boron-containing BNC-1,3-dipole in dipole cycloaddition reactions.

[0027] According to the present invention, preferably, the dipole cycloaddition reaction is a [3+1] cycloaddition reaction, a [3+2] cycloaddition reaction, or a [3+3] cycloaddition reaction;

[0028] More preferably, the substance undergoing the [3+1] cycloaddition reaction is 2,6-dimethylphenylisocyanate, the substance undergoing the [3+2] cycloaddition reaction is carbon disulfide, carbon dioxide, benzophenone, benzonitrile, 2,4,6-trimethylbenzonitrile, or 1,1-stilbene, and the substance undergoing the [3+3] cycloaddition reaction is N-tert-butyl-α-phenylnitrone.

[0029] According to the present invention, preferably, the dipolar cycloaddition reaction is carried out in a solvent; the preferred solvent is toluene or tetrahydrofuran; preferably, the temperature of the dipolar cycloaddition reaction is 15-30°C, more preferably 20-25°C.

[0030] The beneficial effects of this invention are as follows:

[0031] 1. The BNC-1,3-dipolar of this invention contains boron, nitrogen, and carbon, providing a rich variety of elements. The BNC-1,3-dipolar can undergo dipolar cycloaddition reactions with various dipoleophiles to achieve the construction of 4-6 membered heterocycles.

[0032] 2. This invention uses aminobromoborane as a raw material and, under strong alkaline conditions, performs a one-step process to efficiently remove hydrogen bromide and hydrogen abstraction from the precursor compound. The reaction is highly efficient and yields high efficiency. Attached Figure Description

[0033] Figure 1 The compound 2a·(thf)3 obtained in Example 1 1 H-NMR spectrum;

[0034] Figure 2Compound 2a·(thf)3 obtained in Example 1 13 C{ 1 H-NMR spectrum;

[0035] Figure 3 Compound 2a·(thf)3 obtained in Example 1 11 B-NMR spectrum;

[0036] Figure 4 The compound 3a·(thf)3 obtained in Example 2 1 H-NMR spectrum;

[0037] Figure 5 The compound 3a·(thf)3 obtained in Example 2 13 C{ 1 H-NMR spectrum;

[0038] Figure 6 The compound 3a·(thf)3 obtained in Example 2 11 B-NMR spectrum;

[0039] Figure 7 The compound 4a·(thf)2 obtained in Example 3 1 H-NMR spectrum;

[0040] Figure 8 The compound 4a·(thf)2 obtained in Example 3 13 C{ 1 H-NMR spectrum;

[0041] Figure 9 The compound 4a·(thf)2 obtained in Example 3 11 B-NMR spectrum;

[0042] Figure 10 The compound 5a·(thf) obtained in Example 4 1 H-NMR spectrum;

[0043] Figure 11 The compound 5a·(thf) obtained in Example 4 13 C{ 1 H-NMR spectrum;

[0044] Figure 12 The compound 5a·(thf) obtained in Example 4 11 B-NMR spectrum;

[0045] Figure 13 The compound 6a·(thf)2 obtained in Example 5 1 H-NMR spectrum;

[0046] Figure 14 The compound 6a·(thf)2 obtained in Example 5 13 C{ 1 H-NMR spectrum;

[0047] Figure 15 The compound 6a·(thf)2 obtained in Example 5 11 B-NMR spectrum. Detailed Implementation

[0048] This invention provides a BNC-1,3-dipole, its synthesis method, and its uses.

[0049] The BNC-1,3-dipole of the present invention has the structure shown in Formula I:

[0050]

[0051] In Formula I, R1 is a sterically hindered aryl or alkyl group, and R2 and R3 are selected from alkyl or aryl groups. R2 and R3 may be the same or different.

[0052] In one or more preferred embodiments, R1 is selected from 2,6-diphenylphenyl (Dpp), 2,6-bis(2,4,6-trimethylphenyl)phenyl (Dmp), or 2,4,6-tritert-butylphenyl (Mes). * R2 and R3 are fluorene groups.

[0053] According to the present invention, the method for synthesizing the BNC-1,3-dipole includes the following steps:

[0054]

[0055] Under a nitrogen atmosphere, precursor compound 1 was added to a solvent, and a base was added at low temperature. The temperature was then increased to react, and the solid was obtained by filtration and purification to obtain the target BNC-1,3-dipole 2.

[0056] The precursor compound 1 has the structure shown in Formula II:

[0057]

[0058] The meanings of R1, R2, and R3 in Equation II are the same as those in Equation I.

[0059] According to the present invention, precursor compound 1 can be prepared according to existing technical routes:

[0060] Preferred precursor compound 1 has the following structure and is obtained by the following preparation method:

[0061]

[0062] Under a nitrogen atmosphere, R1BBr2 was dissolved in a solvent, followed by the addition of an amine and triethylenediamine (DABCO). The temperature was then increased to react the mixture, and the solid was obtained by filtration and purification to obtain precursor compound 1.

[0063] In one or more preferred embodiments, the solvent is a mixture of tetrahydrofuran (THF) and hexane (Hex); more preferably, the volume ratio of the mixed solvent is v(THF):v(Hex) = 1:5.

[0064] In one or more preferred embodiments, the low-temperature conditions are from -78°C to 0°C.

[0065] In one or more preferred embodiments, the base is lithium diisopropylamino (LDA), which can remove hydrogen bromide and hydrogen from carbon atoms in the molecular structure.

[0066] Preferably, the molar ratio of precursor compound 1 to base is 1:2.

[0067] In one or more preferred embodiments, the reaction temperature is 20°C.

[0068] In one or more preferred embodiments, the purification process is as follows: the filtered solid is washed with pentane solvent and then the solvent is removed.

[0069] According to the present invention, the use of the above-mentioned BNC-1,3-1,3-dipole in dipole cycloaddition reactions.

[0070] In one or more preferred embodiments, the dipole cycloaddition reaction is a [3+1] cycloaddition reaction, a [3+2] cycloaddition reaction, or a [3+3] cycloaddition reaction;

[0071] More preferably, the substance undergoing the [3+1] cycloaddition reaction is 2,6-dimethylphenylisocyanate, the substance undergoing the [3+2] cycloaddition reaction is carbon disulfide, carbon dioxide, benzophenone, benzonitrile, 2,4,6-trimethylbenzonitrile, or 1,1-stilbene, and the substance undergoing the [3+3] cycloaddition reaction is N-tert-butyl-α-phenylnitrone.

[0072] In one or more preferred embodiments, the dipolar cycloaddition reaction is carried out in a solvent; the preferred solvent is toluene or tetrahydrofuran; preferably, the temperature of the dipolar cycloaddition reaction is 15-30°C, more preferably 20-25°C.

[0073] The present invention will be further described below with reference to specific embodiments and accompanying drawings, but is not limited thereto.

[0074] Example 1: Synthesis of BNC-1,3-dipolar 2a·(thf)3

[0075] The synthesis route is as follows:

[0076]

[0077] Under a nitrogen atmosphere, precursor compound 1a was added to a mixed solvent of tetrahydrofuran and hexane, with an optimal volume ratio of v(THF):v(Hex) = 1:5. Then, two equivalents of lithium diisopropylamino (LDA) were slowly added dropwise to the mixed solution at a low temperature of -78°C, followed by gradual warming to room temperature. The precipitate was filtered, and the solvent was dried under vacuum. The resulting viscous solid was washed twice with cold pentane, and the solvent was dried under vacuum to obtain the target compound 2a·(thf)3. 1 H NMR (500MHz, C6D6): δ = 8.19 (d, J = 8Hz, 2H, Ar-H), 7.33 (td, J = 7.5, 0.5Hz, 2H, Ar-H), 7.26 (t, J = 7.5Hz, 1H, Ar-H), 7.08 (d, J = 8Hz, 2H, Ar-H), 7.07-7.05(m,6H,Ar-H),7.00(t,J=7.5Hz,2H,Ar-H),2.99(m,12H,THF-CH2),2.49(s,6H,CH3),2.25(s,12H,CH3),1.23(m,12H,THF-CH2); 13 CNMR (126MHz, C6D6): δ = 147.38 (C q ),140.80(C q ),136.87(C q ),136.08(C q ),130.37(C q ),128.96(CH),128.92(CH),127.28(CH),121.24(CH),119.90(CH),117.61(C q ),116.26(CH),112.23(CH),67.83(THF-CH2),25.43(THF-CH2),21.51(CH3),21.10(CH3),BC was notobserved; 11 B NMR (160MHz, C6D6): δ = 9.38; HRMS (ESI): m / z calcd for C 37 H 34 BNLi: 510.2944 [(M+H)] + ;found:510.2973.

[0078] Example 2: [3+1] Cycloaddition Reaction

[0079] The reactant is 2,6-dimethylphenylisocyanate, and the reaction product is compound 3a·(thf)3, with the following structure:

[0080]

[0081] Compound 2a·(thf)3 was dissolved in toluene under a nitrogen atmosphere, followed by the addition of an equimolar amount of 2,6-dimethylphenylisocyanate at room temperature, and the reaction was stirred for 1 hour at room temperature. After the reaction was complete, the solvent was directly evaporated to obtain an orange powder, compound 3a·(thf)3, in 95% yield. 1 H NMR (500MHz, C6D6): δ = 7.48 (t, J = 7.5Hz, 1H, Ar-H), 7.26 (d, J = 7.5Hz, 2H, Ar-H ),7.17-7.16(m,2H,Ar-H),7.07-7.00(m,8H,Ar-H),6.64(d,J=6Hz,2H,Ar-H), 6.53(t,J=7.5Hz,1H,Ar-H), 6.44(d,J=7Hz,2H,Ar-H), 3.08(m,12H,THF-CH2), 2.51(s,12H,CH3),2.40(s,6H,CH3),1.56(s,6H,CH3),1.15(m,12H,THF-CH2); 13 C NMR (126MHz, C6D6): δ = 152.66 (C q ),149.33(C q ),145.53(C q ),143.25(C q ),139.47(C q ),136.90(C q ),135.59(C q ),128.27(CH),127.97(CH),126.72(CH),126.31(CH),126.14(CH),125.96(C q ),125.57(CH),124.99(CH),121.37(CH),118.92(CH),89.88(C q ),67.83(THF-CH2),25.32(THF-CH2),22.10(CH3),21.41(CH3),18.80(CH3), BC was not observed; 11BNMR(160MHz,C6D6):δ=45.31.HRMS(ESI):m / z calcd for C 46 H 43 BN₂Li: 641.3679 [(M+H)] + Found: 641.3718.

[0082] Example 3: [3+2] Cycloaddition Reaction

[0083] The reactant is 1,1-stilbene, and the reaction product is compound 4a·(thf)2, with the following structure:

[0084]

[0085] Compound 2a·(thf)3 was dissolved in toluene under a nitrogen atmosphere, followed by the addition of an equimolar amount of 1,1-stilbene at room temperature, and the reaction was stirred for 2 hours at room temperature. After the reaction was complete, the solvent was directly evaporated to obtain an orange-red powder, compound 4a·(thf)2, with a yield of 92%. 1 H NMR (500MHz, C6D6): δ = 7.43 (t, J = 7.5Hz, 1H, Ar-H), 7.29 (d, J = 7Hz, 2H, Ar-H), 7.26 (d, J = 7Hz, 4H, Ar- H),7.17(d,J=7.5Hz,2H,Ar-H),6.95(t,J=7Hz,4H,Ar-H),6.91(td,J=7.5,1Hz,2H,Ar-H),6.87(t,J =7.5Hz,2H,Ar-H),6.79(s,4H,Ar-H),6.76(td,J=7.5,1Hz,2H,Ar-H),6.47(d,J=7.5Hz,2H,Ar-H),3 .15(m,12H,THF-CH2),2.34(s,12H,CH3),2.11(s,6H,CH3),1.93(s,2H,CH2),1.26(m,12H,THF-CH2); 13 C NMR (126MHz, C6D6): δ = 157.70 (C q ),150.70(C q ),146.57(C q ),145.46(C q ),140.61(C q ),136.20(C q ),135.64(C q),130.72(CH),128.14(CH),128.07(CH),127.50(CH),126.77(CH),126.65(CH),126.56(CH),126.17(CH),124.74(CH),118.54(CH),90.58(C q ), 67.73 (THF-CH2), 65.87 (C q ),39.55(CH2,determined by HSQC),25.49(THF-CH2),21.72(CH3),20.98(CH3),BC was not observed; 11 B NMR (160MHz, C6D6): δ = 47.95. HRMS (ESI): m / z calcdfor C 51 H 46 BNLi: 690.3883 [(M+H)] + ;found:690.3856.

[0086] Example 4: [3+3] Cycloaddition Reaction

[0087] The reactant is N-tert-butyl-α-phenylnitrone, and the reaction product is compound 5a·(thf), with the following structure:

[0088]

[0089] Compound 2a·(thf)3 was dissolved in toluene under a nitrogen atmosphere, followed by the addition of an equimolar amount of N-tert-butyl-α-phenylnitrone at room temperature, and the reaction was stirred for 2 hours at room temperature. After the reaction was complete, the solvent was directly dried to obtain an orange-red powder, compound 5a·(thf), in 94% yield. 1H NMR(500MHz,C6D6):δ=7.39(d,J=7.5Hz,2H,Ar-H),7.36-7.32(m,2H,Ar-H),7.14-7.10(m,5H,Ar-H),7.08-7.03(m,2H,Ar-H),7.00(d,J=12.5Hz,4H,Ar-H),6.91(t,J=7.5Hz,1H,Ar-H),6.74-6.61(m,4H,Ar-H),6.41(d,J=7.5Hz,1H,Ar-H),3.91(s,1H,NH),3.22(m,12H,THF-CH2),2.43(s,6H,CH3),2.42(s,6H,CH3),2.31(s,6H,CH3),1.25(m,12H,THF-CH2),1.01(s,9H,C(CH3)3); 13 C NMR(126MHz,C6D6):δ=157.40(C q ),155.66(C q ),144.83(C q ),144.16(C q ),141.49(C q ),140.49(C q ),139.97(C q ),136.37(CH),135.99(CH),135.61(CH),131.43(CH),130.57(CH),128.96(CH),128.68(CH),128.58(CH),127.90(CH),126.88(CH),126.81(CH),126.76(CH),126.41(CH),126.32(CH),126.04(CH),125.94(CH),124.70(CH),118.74(CH),117.97(CH),74.00(C q ),72.94(CH),67.86(THF-CH2),60.69(C(CH3)3),28.33(CH3),25.51(THF-CH2),22.04(CH3),21.98(CH3),21.34(C(CH3)3),B-C was not observed; 11 B NMR(160MHz,C6D6):δ=31.04.HRMS(ESI):m / z calcd for C 48 H 49 BN2OLi:687.4098[(M+H)] +;found:687.4129.

[0090] Example 5: Boron-centered nucleophilic reaction

[0091] The reactant is adamantane azide, and the reaction product is compound 6a·(thf)2, with the following structure:

[0092]

[0093] Compound 2a·(thf)3 was dissolved in toluene under a nitrogen atmosphere, followed by the addition of an equimolar amount of adamantane azide at room temperature, and the reaction was stirred for 1 hour at room temperature. After the reaction was complete, the solvent was directly evaporated to obtain an orange-red powder, compound 6·(thf)2, with a yield of 95%. 1 H NMR (500MHz, C6D6): δ = 7.35 (t, J = 7.5Hz, 1H, Ar-H), 7.33 (d, J = 7.5Hz, 2H, Ar-H) ,7.22(d,J=7.5Hz,2H,Ar-H),7.13-7.10(m,4H,Ar-H),7.02(t,J=7.5Hz,2H,Ar- H),6.85(s,4H,Ar-H),3.29(m,16H,THF-CH2),2.40(s,12H,CH3),2.30(s,6H,CH 3),2.09(s,3H,CH),1.89(s,6H,CH2),1.71(s,6H,CH2),1.28(m,16H,THF-CH2); 13 CNMR (126MHz, C6D6): δ = 154.00 (C q ),145.23(C q ),143.11(C q ),142.49(C q ),137.72(C q ),136.98(C q ),134.96(C q ),129.91(CH),128.09(CH),127.64(CH),127.43(CH),127.34(CH),125.05(CH),119.20(CH),67.94(THF-CH2),58.73(C q ),42.98(CH2),37.43(CH2),30.19(CH),25.49(THF-CH2),22.45(CH3),21.47(CH3), BC was not observed; 11B NMR(160MHz,C6D6):δ=36.20.HRMS(ESI):m / z calcd for C 47 H 49 BN4Li:687.4210[(M+H)] + ;found:687.4200。

Claims

1. A BNC-1,3-dipole, characterized in that, The BNC-1,3-dipole has the structure shown in Equation I: In Formula I, R1 is a sterically hindered aryl or alkyl group, and R2 and R3 are selected from alkyl or aryl groups. R2 and R3 may be the same or different.

2. The BNC-1,3-dipole according to claim 1, characterized in that, R1 is selected from 2,6-diphenylphenyl (Dpp), 2,6-bis(2,4,6-trimethylphenyl)phenyl (Dmp), or 2,4,6-tritert-butylphenyl (Mes). * R2 and R3 are fluorene groups.

3. The method for synthesizing BNC-1,3-dipoles according to claim 1 or 2, comprising the following steps: Under a nitrogen atmosphere, the precursor compound aminoboron bromide 1 was added to a solvent, and a base was added at low temperature. The temperature was then increased to react, and the solid was obtained by filtration and purification to obtain the target compound BNC-1,3-dipole 2. The precursor compound 1 has the structure shown in Formula II: The meanings of R1, R2, and R3 in Equation II are the same as those in Equation I.

4. The method for preparing BNC-1,3-dipoles according to claim 3, characterized in that, The solvent is a mixture of tetrahydrofuran and hexane; preferably, the volume ratio of the mixed solvent is v(THF):v(Hex) = 1:

5. Preferably, the alkali is lithium diisopropylamino.

5. The method for preparing BNC-1,3-dipoles according to claim 3, characterized in that, The low-temperature conditions are from -78°C to 0°C; preferably, the reaction temperature is 20°C.

6. The method for preparing BNC-1,3-dipoles according to claim 3, characterized in that, The molar ratio of precursor compound 1 to the base is 1:

2.

7. The method for preparing BNC-1,3-dipoles according to claim 3, characterized in that, The purification process is as follows: the filtered solid is washed with pentane solvent and then the solvent is removed.

8. Use of the BNC-1,3-dipolar as described in any one of claims 1-2 in a dipole cycloaddition reaction.

9. The use according to claim 8, characterized in that, The aforementioned dipolar cycloaddition reactions are [3+1] cycloaddition reactions, [3+2] cycloaddition reactions, and [3+3] cycloaddition reactions.

10. The use according to claim 9, characterized in that, The substance undergoing the [3+1] cycloaddition reaction is 2,6-dimethylphenylisocyanate; the substance undergoing the [3+2] cycloaddition reaction is carbon disulfide, carbon dioxide, benzophenone, benzonitrile, 2,4,6-trimethylbenzonitrile, and 1,1-stilbene; and the substance undergoing the [3+3] cycloaddition reaction is N-tert-butyl-α-phenylnitrone.

Images