Synthesis method of central chiral aza seven-membered bridged biaryl compound containing chiral axis

Abstract

The invention provides a synthesis method of a chiral-axis-containing central chiral aza-seven-membered bridged biaryl compound, which comprises the following steps: under the action of a palladium catalyst, a chiral assistant and an additive, firstly carrying out a carbon-hydrogen bond activation reaction on a benzidine compound under the action of the palladium catalyst, and then reacting with 1, 3-dichlorobenzidine to obtain a chiral-axis-containing central chiral aza-seven-membered bridged biaryl compound. The method comprises the following steps: carrying out asymmetric [5 + 2] cyclization reaction on 1, 3-conjugated diene to obtain a central chiral bridged biaryl compound containing a chiral axis; according to the invention, a palladium-catalyzed asymmetric carbon-hydrogen bond activation / [5 + 2] cyclization method is adopted, so that a new way is provided for synthesizing a chiral seven-membered bridged biaryl structure with fewer reports; sulfoxide oxazoline containing a double chiral source is used as a chiral auxiliary agent, and a single axial product with high diastereoselectivity is obtained in a chiral transfer manner through reaction; the substrate applicability is wide, and a series of central chiral seven-membered bridged biaryl compounds containing chiral shafts are synthesized in a high-yield and high-enantioselectivity manner; the synthesis method is efficient and high in atom economy.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, and in particular to a method for constructing a centrally chiral nitrogen-based seven-membered bridged aromatic compound containing a chiral axis by palladium-catalyzed asymmetric C-H bond activation / [5+2] cyclization. Background Technology

[0002] Over the past decade, axially chiral compounds have become a research hotspot for scientists because they can serve as highly efficient chiral ligands in asymmetric reactions. Among these, trans-restricted isomers are the most representative form of axial isomerism, primarily exhibiting enantiomerism resulting from the inability of the σ-single bond to rotate freely due to steric hindrance from substituents or electronic effects. In particular, because the two adjacent sites on the same side of the axis are firmly bound by aliphatic chains, bridged biaromatic structures exhibit trans-restricted isomerism as the ring system increases and substituents are added. Structures containing five- or six-membered ring systems typically have lower flip energy barriers, and their rotation is not hindered, while bridged biaromatic structures containing seven- or higher-membered rings exhibit trans-restricted stability. More interestingly, a relay phenomenon from central chirality to axial chirality is often observed in seven-membered bridged biaromatic structures, where the axial chiral configuration is controlled by the central chiral configuration of the bridging carbon atom.

[0003] Aza-bridged aromatic compounds are also an important class of structural units, widely found in natural products and bioactive reagents. For example, LY-411575 is a highly effective γ-secretase inhibitor with various biological activities; microtubuline inhibitors are microtubule inhibitors that can inhibit cancer cell proliferation. In addition, scientists have synthesized chiral reagents with this type of skeleton for use in asymmetric catalytic reactions, exhibiting excellent chiral induction effects. Compared to the asymmetric synthesis research of other structural compounds, chemists have conducted relatively little research on the asymmetric synthesis of this type of structure, thus necessitating the development of an efficient and convenient synthetic method.

[0004] Currently, several synthetic reports exist in the field of asymmetric synthesis: Cramer's group reported palladium-catalyzed intramolecular desymmetry reactions (Cramer, N. Angew. Chem. 2013, 125, 8019) and asymmetric cyclization reactions (Cramer, N. Angew. Chem. Int. Ed. 2018, 57, 11040) to construct dibenzozaheptanone. Subsequently, Zhu Qiang's group successively used palladium-catalyzed asymmetric cyclization / carbonylation methods (Zhu, Q. Org. Lett. 2021, 23, 3636) and palladium-catalyzed Heck cyclization and small molecule-catalyzed asymmetric hydrogen sulfidation stepwise methods for synthesis (Zhu, Q. Org. Lett. 2022, 24, 3642). Meanwhile, the research groups of Yin Qin (Yin, Q. Org. Lett. 2020, 22, 6479) and Zhang Xumu (Zhang, X. Chem. Sci. 2019, 10, 2473) have collaborated to develop methods for cyclization and asymmetric hydrogenation. However, these methods are limited to the use of specific reaction substrates or multi-step synthetic routes. Therefore, the one-step synthesis of axially stable chiral aza-bridged biaromatic compounds using simple reaction substrates has significant practical significance and application prospects.

[0005] In recent years, asymmetric C-H bond activation has made significant progress in the synthesis of various chiral molecules. Therefore, using benzidine-like compounds as the nitrogen source and 1,3-conjugated dienes as the C2 reagent, the direct construction of centrally chiral azahexa-bridged biaromatic compounds with chiral axes via palladium-catalyzed asymmetric C-H bond activation / cyclization is highly feasible. Adding a suitable chiral auxiliary agent during the reaction induces the generation of chiral centers, thereby transferring chirality to construct the chiral axis. However, the axis flipping energy barrier is low, axial control is difficult, and the design of chiral auxiliaries is highly demanding. Summary of the Invention

[0006] This invention provides a method for constructing centrally chiral azirionic seven-membered bridged aromatic compounds containing a chiral axis through palladium-catalyzed asymmetric C-H bond activation / [5+2] cyclization. This invention uses a transition metal palladium salt as a catalyst, sulfoxide oxazoline containing bipolar sources as a chiral auxiliary, and inexpensive and readily available benzidines and 1,3-conjugated dienes to efficiently synthesize centrally chiral azirionic seven-membered bridged aromatic compounds containing a chiral axis, further improving the synthetic efficiency.

[0007] The technical solution of this invention is: a method for synthesizing a centrally chiral aza-bridged seven-membered aromatic compound containing a chiral axis, wherein the method is as follows:

[0008] In the presence of a palladium catalyst, a chiral auxiliary agent, additives, and a solvent, benzidine substrates undergo an asymmetric C-H bond activation / [5+2] cyclization reaction with 1,3-conjugated dienes. After the reaction, the resulting chiral, centrally chiral, nitrogen-bridged, seven-membered aromatic compounds with a chiral axis are obtained through appropriate separation. The synthetic method is as follows:

[0009]

[0010] In the formula, Ar 1 The phenyl group is a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the para position; a phenyl group containing multiple C1-C4 alkyl groups at the meta position; or a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the ortho position; the heteroatom group is selected from one of halogen, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, acetyl, 1,4-oxazolidinyl, or trimethylsilyl; or Ar 1 The phenyl group is replaced by an estrone group, a C6 non-aromatic group, a benzo[a] heterocyclic group, or a fused ring group. The benzo[a] heterocyclic group is selected from one of the benzothiophene group, the indole group, and the benzo[a] dioxane group. The fused ring group is selected from one of the naphthyl group and the benzo[a] phenanthrene group.

[0011] Ar 2 The phenyl group is a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the ortho or meta position, or a phenyl group containing a nitro group at the para position; the heteroatom group is selected from one of the halogen or C1 alkoxy groups; or Ar 2 Replace phenyl with naphthyl;

[0012] Ar 3 The phenyl group is a phenyl group containing a C1-C4 alkyl group or a heteroatom group at the para position, and a phenyl group containing one or more C1-C4 alkyl groups at the ortho and meta positions; the heteroatom group is selected from one of halogen, C1-C6 alkoxy, nitro, trimethylsilyl, 1,4-oxazolidinyl, and diphenylamino; or Ar 3 The phenyl group is replaced by a ferrocene group, a benzo[a]heterocyclic group, a fused ring group, or a C1-C6 alkyl group. The benzo[a]heterocyclic group is selected from one of a benzo[a]furan group or a dibenzo[a]furan group, and the fused ring group is selected from one of a naphthyl group or a pyrene group.

[0013] During the reaction, by controlling the reaction with chiral auxiliaries, the products of the asymmetric C-H bond activation reaction can have an ee value of 70% to 95% and a dr value of >20 / 1.

[0014] Preferably, the additive is composed of an oxidizing agent, Oxidant, and the reaction formula is as follows:

[0015]

[0016] In the formula, Ar 1It is a phenyl group, and phenyl groups containing methyl, isopropyl, n-butyl, methoxy, methoxycarbonyl, acetyl, fluorine, 1,4-oxazolidinyl, phenyl, or trimethylsilyl groups at the ortho, meta, or para positions, or Ar. 1 The benzene ring is replaced by an estradiol group, a cyclohexene group, a benzofuran group, an indole group, a benzodioxane group, a naphthyl group, or a benzophenanthrene group;

[0017] Ar 2 It is a phenyl group, and phenyl groups containing phenyl, methyl, methoxy, fluorine, or nitro groups at the ortho, meta, or para positions, or Ar. 2 Replace phenyl with naphthyl;

[0018] Ar 3 It is a phenyl group, and phenyl groups containing methyl, isopropyl, tert-butyl, methoxy, phenoxy, trimethylsilyl, fluorine, nitro, 1,4-oxazolidinyl, or diphenylamino groups at the ortho, meta, or para positions, or Ar 3 The phenyl group can be replaced by naphthyl, pyrene, ferrocene, benzofuran, dibenzofuran, cyclohexyl, or methyl.

[0019] Preferably, the molar ratio of the benzidine substrate, 1,3-conjugated diene substrate, palladium catalyst, chiral auxiliary agent, and oxidant is 1:1.0-2.0:0.05-0.15:0.05-0.3:1.0-3.0, and more preferably 1:1.5:0.05:0.1:1.

[0020] Preferably, the benzidine substrate undergoes an asymmetric C-H bond activation / [5+2] cyclization reaction with a 1,3-conjugated diene, and after post-treatment, a centrally chiral azaheptene-bridged synaromatic compound containing a chiral axis is obtained.

[0021] Preferably, the oxidant Oxidant is copper acetate and manganese acetate tetrahydrate in a molar ratio of 1:0.5 to 2.0.

[0022] Preferably, the palladium catalyst is palladium acetate.

[0023] Preferably, the chiral auxiliary is a chiral sulfoxide oxazoline with the following structural formula:

[0024]

[0025] Wherein, the Ar-labeled benzene ring represents a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is selected from one or more C1-C4 alkyl or C1-C4 alkoxy groups, more specifically, preferably (R)-4-phenyl-2-(3,4,5-trimethoxy-2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole.

[0026] Preferably, the solvent is 2-methyl-2-butanol and water, and the amount of solvent is: 1-5 mL of 2-methyl-2-butanol and 0-50 μL of water per 0.1 mmol of benzidine substrate, more preferably 1 mL of 2-methyl-2-butanol and 5 μL of water.

[0027] Preferably, the temperature of the asymmetric C-H bond activation / [5+2] cyclization reaction is 80-100°C and the reaction time is 24-48 hours. More preferably, the temperature of the asymmetric C-H bond activation / [5+2] cyclization reaction is 90°C and the reaction time is 24 hours.

[0028] Preferably, the separation process is as follows:

[0029] After the reaction was completed, the product was obtained by filtration through a diatomaceous earth pad, concentration of the filtrate under reduced pressure, and separation by thin-layer silica gel plate chromatography.

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

[0031] 1. This invention uses benzidine compounds and 1,3-conjugated dienes as raw materials, transition metal palladium as a catalyst, and chiral sulfoxide oxazoline as a chiral auxiliary to synthesize a centrally chiral nitrogen-based seven-membered bridged aromatic compound containing a chiral axis through asymmetric C-H bond activation / [5+2] cyclization.

[0032] 2. This invention achieves the synthesis of chiral nitrogen-based seven-membered bridged aromatic compounds with chiral axes through a transition metal-catalyzed asymmetric C-H bond activation / [5+2] cyclization, thus expanding the synthetic pathways for chiral seven-membered bridged aromatic structures.

[0033] 3. This invention obtains a highly diastereoselective single-axial product by controlling the chirality of chiral sulfoxide oxazoline through chiral transfer.

[0034] 4. This invention synthesizes a variety of centrally chiral aza-bridged biaromatic compounds with chiral axes. These compounds have broad substrate adaptability, strong stereoselectivity of products, simple synthesis methods, good atom economy, and high synthesis efficiency. Attached Figure Description

[0035] Figure 1 The HPLC chromatograms of compound 1 and its racemic mixture obtained in Example 1 are shown. The HPLC conditions were as follows: IG column, mobile phase: hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm.

[0036] Figure 2The HPLC chromatograms of compound 22 and its racemic mixture obtained in Example 22 are shown. The HPLC conditions were as follows: IG column, mobile phase: hexane / isopropanol = 92 / 8, flow rate = 1.0 mL / min, λ = 254 nm. Detailed Implementation

[0037] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings:

[0038] Example 1

[0039] In a reactor, 0.1 mmol of N-trifluoromethanesulfonamide-1,1'-biphenyl, 0.15 mmol of (E)-1-phenyl-1,3-butadiene, 0.005 mmol of palladium acetate, 0.01 mmol of chiral auxiliary (R)-4-phenyl-2-(3,4,5-trimethoxy-2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole, 0.1 mmol of copper acetate, 0.1 mmol of manganese acetate tetrahydrate, a magnetic stir bar, 1 mL of 2-methyl-2-butanol, and 5 μL of water were added. The reactor was placed on an aluminum heating module and heated at 90 °C for 24 hours. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. Preparative-grade thin-layer chromatography yielded product 1 with the structure of Formula 1, in 95% yield and ee value of 94%. The HPLC chromatograms of compound 1 and its racemic mixture are shown in [Figure number missing]. Figure 1 .

[0040] The structure of product 1 is as follows:

[0041]

[0042] 1 H NMR (400MHz, CDCl3) δ7.58-7.55(m,1H),7.55-7.51(m,1H),7.51-7.41(m,6H),7.38-7.25(m,5H),6.73(d,J=15.9Hz, 1H), 6.30 (dd, J = 15.9, 7.4Hz, 1H), 5.26 (dt, J = 12.7, 6.2Hz, 1H), 2.89 (dd, J = 14.0, 5.4Hz, 1H), 2.75 (t, J = 13.2Hz, 1H); 13 C NMR (101MHz, CDCl3) δ138.19,135.99,135.30,132.87,132.15,131.85,130.30,129.51,128.79, 128.75,128.70,128.64,128.34,128.11,126.78,126.62,119.38(d,J=323.2Hz),71.44,38.07; 19FNMR (376MHz, CDCl3) δ -76.08. HRMS (ESI) for [C 23 H 18 F3NO2S+Na + Calculated value: 452.0903, Measured value: 452.0903;

[0043] Determination of the 1ee value of the compound: HPLC (Daicel Chiralpak IG column, mobile phase: hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, λ = 254 nm), t r = 5.9 min (peak 1), 13.5 min (peak 2): 94% ee.

[0044] Examples 2-48

[0045] The operation steps are the same as in Example 1, except that by changing the substituents on the raw materials, different chiral aza-heptane-bridged biaromatic products can be obtained, as shown in the table below.

[0046] Table 1. Experimental results of the synthesis of chiral aza-heptagonal bridged polyarenes in Examples 2-48

[0047]

[0048] [a] The reaction time is 48 hours.

[0049] Taking Example 22 as an example, the process is as follows:

[0050] In a reactor, 0.1 mmol of N-trifluoromethanesulfonamide-1,1'-biphenyl, 0.15 mmol of (E)-1-(4-butyl)benzene-1,3-butadiene, 0.005 mmol of palladium acetate, 0.01 mmol of chiral auxiliary (R)-4-phenyl-2-(3,4,5-trimethoxy-2-((S)-p-tolylsulfinyl)phenyl)-4,5-dihydrooxazole, 0.1 mmol of copper acetate, 0.1 mmol of manganese acetate tetrahydrate, a magnetic stir bar, 1 mL of 2-methyl-2-butanol, and 5 μL of water were added. The reactor was placed on an aluminum heating module and heated at 90 °C for 24 hours. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. Preparative-grade thin-layer chromatography yielded product 22 with the structure of Formula 2, in 95% yield and ee value of 94%. The HPLC chromatograms of compound 22 and its racemic mixture are shown in [Figure number missing]. Figure 2 .

[0051] The structure of product 22 is as follows:

[0052]

[0053] 1H NMR (400MHz, CDCl3) δ7.57-7.53(m,1H),7.51-7.50(m,1H),7.47-7.43(m ,4H),7.40-7.37(m,1H),7.36-7.30(m,4H),7.16(s,1H),7.14(s,1H),6.6 9(d,J=15.9Hz,1H),6.25(dd,J=15.9,7.5Hz,1H),5.24(dt,J=12.7,6.4H z,1H),2.88(dd,J=14.0,5.4Hz,1H),2.73(t,J=13.2Hz,1H),2.35(s,3H); 13 C NMR (101MHz, CDCl3) δ138.33,138.20,135.39,133.20,132.77,132.18,131.87,130.28,129.49,129 .41,128.81,128.74,128.63,128.08,126.70,125.58,119.40(d,J=323.5Hz),71.55,38.09,21.29; 19 F NMR (376MHz, CDCl3) δ -76.08.

[0054] HRMS (ESI) for [C 24 H 20 F3NO2S+Na + Calculated value: 466.1059, Measured value: 466.1060;

[0055] Determination of the ee value of compound 22: HPLC (Daicel Chiralpak IG column, mobile phase: hexane / isopropanol = 92 / 8, flow rate = 1.0 mL / min, λ = 254 nm), t r =13.4 min (peak 1), 29.0 min (peak 2): 94% ee.

[0056] The embodiments and descriptions above are merely illustrative of the principles and preferred embodiments of the present invention. Various changes and modifications may be made to the present invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed.

Claims

1. A method for synthesizing a centrally chiral aza-bridged biaromatic compound containing a chiral axis, characterized in that, include: In the presence of a palladium catalyst, a chiral auxiliary agent, additives, and a solvent, benzidine substrates undergo an asymmetric C-H bond activation / [5+2] cyclization reaction with 1,3-conjugated dienes. After the reaction, the resulting compounds are isolated to obtain a centrally chiral aza-bridged syn-aromatic compound containing a chiral axis. The synthesis is as follows: In the formula, Ar 1 The phenyl group is a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the para position; a phenyl group containing multiple C1-C4 alkyl groups at the meta position; or a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the ortho position; the heteroatom group is selected from one of halogen, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, acetyl, 1,4-oxazolidinyl, or trimethylsilyl; or Ar 1 The phenyl group is replaced by an estrone group, a C6 non-aromatic group, a benzo[a] heterocyclic group, or a fused ring group. The benzo[a] heterocyclic group is selected from one of the benzothiophene group, the indole group, and the benzo[a] dioxane group. The fused ring group is selected from one of the naphthyl group and the benzo[a] phenanthrene group. Ar 2 The phenyl group is a phenyl group containing a C1-C4 alkyl group, a heteroatom group, or an aryl group at the ortho or meta position, or a phenyl group containing a nitro group at the para position; the heteroatom group is selected from one of a halogen or a C1-C6 alkoxy group; or Ar 2 Replace phenyl with naphthyl; Ar 3 The phenyl group is a phenyl group containing a C1-C4 alkyl group or a heteroatom group at the para position, and a phenyl group containing one or more C1-C4 alkyl groups at the ortho and meta positions; the heteroatom group is selected from one of halogen, C1-C6 alkoxy, nitro, trimethylsilyl, 1,4-oxazolidinyl, and diphenylamino; or Ar 3 The phenyl group is replaced by a ferrocene group, a benzo[a]heterocyclic group, a fused ring group, or a C1-C6 alkyl group. The benzo[a]heterocyclic group is selected from one of a benzo[a]furan group or a dibenzo[a]furan group, and the fused ring group is selected from one of a naphthyl group or a pyrene group.

2. The method for synthesizing a centrally chiral aza-bridged biaromatic compound containing a chiral axis according to claim 1, characterized in that: In the formula, Ar 1 It is a phenyl group, and phenyl groups containing methyl, isopropyl, n-butyl, methoxy, methoxycarbonyl, acetyl, fluorine, 1,4-oxazolidinyl, phenyl, or trimethylsilyl groups at the ortho, meta, or para positions, or Ar. 1 The benzene ring is replaced by an estradiol group, a cyclohexene group, a benzofuran group, an indole group, a benzodioxane group, a naphthyl group, or a benzophenanthrene group; Ar 2 It is a phenyl group, and phenyl groups containing phenyl, methyl, methoxy, fluorine, or nitro groups at the ortho, meta, or para positions, or Ar. 2 Replace phenyl with naphthyl; Ar 3 It is a phenyl group, and phenyl groups containing methyl, isopropyl, tert-butyl, methoxy, phenoxy, trimethylsilyl, fluorine, nitro, 1,4-oxazolidinyl, or diphenylamino groups at the ortho, meta, or para positions, or Ar 3 The phenyl group can be replaced by naphthyl, pyrene, ferrocene, benzofuran, dibenzofuran, cyclohexyl, or methyl.

3. The method for synthesizing a centrally chiral aza-bridged polyaromatic compound containing a chiral axis according to claim 1, characterized in that: The additive is composed of an oxidizing agent; The oxidizing agent is copper acetate and manganese acetate tetrahydrate, with a molar ratio of 1:0.5 to 2.

0.

4. The method for synthesizing a centrally chiral aza-bridged biaromatic compound containing a chiral axis according to claim 1, characterized in that: The molar ratio of benzidine substrate, 1,3-conjugated diene substrate, palladium catalyst, chiral auxiliary agent, and oxidant is 1:1.0-2.0:0.05-0.15:0.05-0.3:1.0-3.

0.

5. The method for synthesizing a centrally chiral aza-bridged polyaromatic compound containing a chiral axis according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

6. The method for synthesizing a centrally chiral aza-heptagonal bridged compound containing a chiral axis according to claim 1, characterized in that: The chiral adjuvant is a chiral sulfoxide oxazoline, with the following structural formula: Wherein, the Ar-labeled benzene ring represents a substituted or unsubstituted phenyl group, and the substituents on the phenyl group are selected from one or more C1-C4 alkyl or C1-C4 alkoxy groups.

7. The method for synthesizing a centrally chiral aza-heptagonal bridged compound containing a chiral axis according to claim 1, characterized in that: The solvent is 2-methyl-2-butanol and water, and the amount of solvent is: 1-5 mL of 2-methyl-2-butanol and 0-50 μL of water per 0.1 mmol of benzidine substrate.

8. The method for synthesizing a centrally chiral aza-bridged polyaromatic compound containing a chiral axis according to claim 1, characterized in that: The asymmetric C-H bond activation / [5+2] cyclization reaction is carried out at a temperature of 80–100 °C for 24–48 hours.

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