CN115232139B - Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof - Google Patents
Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof Download PDFInfo
- Publication number
- CN115232139B CN115232139B CN202210854077.XA CN202210854077A CN115232139B CN 115232139 B CN115232139 B CN 115232139B CN 202210854077 A CN202210854077 A CN 202210854077A CN 115232139 B CN115232139 B CN 115232139B
- Authority
- CN
- China
- Prior art keywords
- reaction
- cyclopropane
- fused
- benzoxy
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/549—Organic PV cells
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and a synthesis method thereof, wherein a simple and easily obtained o-alkynyl benzaldehyde compound is used as a raw material, and is heated in a solvent in the presence of a gold catalyst for reaction, and after post treatment, the cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound is obtained. The synthesized cyclopropane fused 6/7/7-benzoxy bridged polycyclic compound contains oxygen bridges, cyclopropane and other multifunctional groups, and can be further structurally modified and chemically converted into various compounds.
Description
Technical Field
The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and a synthesis method thereof.
Background
The fused 6/7/7 tricyclic system is a component of the alkaloid rhein, such as Colchicine (Colchicine), which is a unique representative of the alkaloid rhein and is derived from meadow saffron, is a secondary metabolite of autumn saffron, has an anti-inflammatory effect, and is the first reported tubulin destabilizer. Because of its remarkable antimitotic activity, the effect of this compound on various indications has been widely studied, such as for the treatment of various diseases such as acute gout, familial mediterranean fever and chronic myelogenous leukemia. Meanwhile, colchicine is also used as an animal model of neurotoxin for the treatment of senile dementia, epilepsy, pericarditis and behcet's disease. Colchicine and its analogues have also shown significant efficacy in tumor chemotherapy treatment in recent years. The construction of the unusual fused 6/7/7 polycyclic compound has great difficulty, so the novel method for quickly and efficiently constructing the benzoheptatomic cycloheptane compound has important significance.
At present, the method for synthesizing cyclopropane fused 6/7/7-benzoxy bridged polycyclic compounds is quite rare, and the raw material synthesis steps are complex and tedious, and the yield is low. Therefore, how to quickly and efficiently construct the cyclopropane fused 6/7/7 benzoxy bridge polycyclic compounds from the simple and easily available raw materials has important research significance.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the above and/or problems occurring in the prior art.
One of the purposes of the invention is to provide a cyclopropane fused 6/7/7-benzoxy bridged polycyclic compound which contains oxygen bridges, cyclopropane and other multifunctional groups and can be further structurally modified and chemically converted into various compounds.
In order to solve the technical problems, the invention provides the following technical scheme: a cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound has a structural formula shown in a formula (I):
wherein R is 1 One selected from phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, sulfonamide substituted phenyl, C1-C3 alkyl substituted phenyl, naphthyl, C1-C6 alkyl, styryl or phenylethynyl; r is R 2 One selected from hydrogen, halogen, methyl, trifluoromethyl, methoxy and cyano.
The invention also aims to provide a method for synthesizing the cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound, which is characterized in that a compound shown in a formula (II) is taken as a raw material, and the raw material is heated and reacted in a solvent under the catalysis of a gold catalyst to obtain the compound shown in the formula (I);
wherein R in formula (II) 1 、R 2 And R in formula (I) 1 、R 2 The correspondence is consistent.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the gold catalyst is selected from one of catalysts shown in formulas (III) - (VIII);
as a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the molar ratio of the gold catalyst to the compound shown in the formula (II) is 0.03-0.1:1.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the solvent is selected from one of benzene, toluene, dichloroethane and methyl tertiary butyl ether.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the solvent is dichloroethane.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the heating reaction in the solvent also comprises the steps of adding into a reaction system
Molecular sieves.
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the said
The molecular sieve is added in an amount of 50-200 mg per 0.1mmol of the compound represented by the formula (II).
As a preferable scheme of the synthesis method of the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound, the invention comprises the following steps: the reaction temperature is 25-80 ℃ and the reaction time is 12-24 hours.
The cyclopropane fused 6/7/7-benzoxy bridged polycyclic compound prepared by the invention contains oxygen bridges, cyclopropane and other multifunctional groups, and can be further modified in structure and chemically converted into various compounds.
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages that the raw materials are simple and easy to obtain, the high-efficiency construction of the cyclopropane fused 6/7/7 benzo-oxygen-bridge polycyclic compound with larger tension, which is difficult to construct by the conventional method, can be realized, and the reaction can construct four continuous chiral centers in one step and has excellent stereoselectivity. The method has the advantages of easily available raw materials, simple operation, low catalyst loading, mild conditions, wide substrate range, high yield and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the target product 1a prepared in example 1 of the present invention;
FIG. 3 is a schematic view showing the reaction mechanism represented by the raw material 2a in example 1 of the present invention;
FIG. 4 is a single crystal diffraction pattern of 1g of the objective product prepared in example 7 of the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The raw material o-alkynylbenzaldehyde compound used in the examples, the method reported in reference (Chemical Science 2021,12,1544-1550) was synthesized simply from 2-allylallyl alcohol (Journal of Organometallic Chemistry,1979,168,1-11) and o-iodobenzaldehyde derivative by a two-step method.
Example 1
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2a (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 11/1, V/V) to give the desired product 1a (76 mg, white solid, yield 80%).
The reaction equation is:
the above target product 1a was characterized as shown in fig. 1 and 2.
1 H NMR(600MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.33–7.29(m,4H),7.26–7.22(m,2H),7.20(d,J＝7.5Hz,1H),7.18(d,J＝6.5Hz,1H),7.16(dd,J＝7.4,1.0Hz,1H),7.08(d,J＝7.3Hz,1H),6.69(s,1H),4.96(d,J＝5.9Hz,1H),4.33(d,J＝14.1Hz,1H),3.98(d,J＝14.4Hz,1H),3.86(d,J＝14.4Hz,1H),3.67(d,J＝14.1Hz,1H),2.86(s,2H),2.45(s,1H),2.44(s,1H),1.88(dd,J＝11.6,6.0Hz,1H),1.15(d,J＝11.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.4,136.6,135.3,134.5,132.4,131.6,129.7,128.5,128.4,127.8,127.3,127.2,126.8,124.9,122.1,75.6,64.8,58.5,48.4,33.5,30.2,26.1,26.0,21.5.
The reaction mechanism of the present invention is represented by the raw material 2a as shown in FIG. 3.
First, the carbon-carbon triple bond in 2a and gold catalyst SIMesaAuNTf 2 Complexing to form complex A, then carrying out intramolecular 6-endo-dig cyclization to form gold-complexed pyrylium intermediate B or resonance type C thereof, and then carrying out intramolecular [3+2 ] with allylic double bond]Cycloaddition reaction to form the oxygen-bridged gold carbene intermediate D, followed by C (sp 3 ) H intercalation gives the final product 1a, while releasing the gold catalyst.
Example 2
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2b (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 9/1, V/V) to give the objective product 1b (80 mg, white solid, yield 82%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.75(d,J＝8.2Hz,2H),7.32(d,J＝8.1Hz,2H),7.27–7.25(m,1H),7.19–7.16(m,4H),7.09(d,J＝7.3Hz,1H),6.99(t,J＝8.6Hz,2H),6.65(s,1H),4.96(d,J＝5.9Hz,1H),4.33(d,J＝14.1Hz,1H),3.99(d,J＝14.3Hz,1H),3.83(d,J＝14.3Hz,1H),3.63(d,J＝14.1Hz,1H),2.83(s,2H),2.45(s,3H),2.43(s,1H),1.88(dd,J＝11.6,6.0Hz,1H),1.15(d,J＝11.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ161.8(d,J＝247.0Hz),143.4,136.6,135.3,134.6,132.6(d,J＝3.4Hz),132.3,130.5,130.2(d,J＝7.9Hz),129.7,127.8,127.3,126.7,125.0,122.1,115.4(d,J＝21.5Hz),75.6,64.7,58.3,48.4,33.5,30.2,26.1,25.9,21.5.
example 3
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2c (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 9/1, V/V) to give the objective product 1c (68 mg, white solid, yield 63%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.75(d,J＝7.7Hz,2H),7.56(d,J＝7.9Hz,2H),7.32(t,J＝8.7Hz,4H),7.28–7.25(m,1H),7.20–7.16(m,2H),7.09(d,J＝7.3Hz,1H),6.72(s,1H),4.97(d,J＝5.8Hz,1H),4.38(d,J＝14.3Hz,1H),4.04(d,J＝14.3Hz,1H),3.81(d,J＝14.3Hz,1H),3.63(d,J＝14.3Hz,1H),2.87–2.81(m,2H),2.45(s,4H),1.88(dd,J＝11.5,5.9Hz,1H),1.15(d,J＝11.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.5,140.2,136.8,136.5,135.2,132.2,130.1,129.7,128.8,127.9,127.3,126.7,125.4,125.3,125.1,124.9,122.1,75.5,64.6,58.1,48.5,33.5,30.3,26.1,25.9,21.5； 19 F NMR(565MHz,CDCl 3 )δ-62.54.
example 4
A10 mL round bottom flask was taken and was charged with O-alkynyl benzaldehyde 2d (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 9/1, V/V) to give the objective product 1d (72 mg, white solid, yield 75%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.32(d,J＝8.1Hz,2H),7.26–7.24(m,1H),7.18–7.15(m,2H),7.11–7.08(m,5H),6.65(s,1H),4.95(d,J＝6.0Hz,1H),4.30(d,J＝14.1Hz,1H),3.95(d,J＝14.4Hz,1H),3.87(d,J＝14.4Hz,1H),3.68(d,J＝14.0Hz,1H),2.88–2.82(m,2H),2.45(s,3H),2.42(s,1H),2.32(s,3H),1.88(dd,J＝11.6,6.0Hz,1H),1.15(d,J＝11.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.3,136.9,136.6,135.3,133.7,132.5,131.7,129.7,129.1,128.5,127.8,127.3,126.8,124.9,122.1,75.6,64.8,58.6,48.4,33.5,30.2,26.2,26.1,21.5,21.1.
example 5
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2e (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 (0.01 mmol) and under argon atmosphere, two were addedEthyl chloride (4 mL), at 60 ℃ for 12 hours, cooling to room temperature after the reaction is finished, filtering to remove a molecular sieve, rotationally evaporating and concentrating filtrate to remove a solvent, and separating a crude product by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=20/1-9/1, V/V) to obtain a target product 1e (84 mg, white solid, yield 81%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.81–7.78(m,4H),7.72–7.70(m,1H),7.68(s,1H),7.47–7.44(m,2H),7.36–7.33(m,3H),7.27–7.25(m,1H),7.21(d,J＝7.2Hz,1H),7.18(td,J＝7.4,1.1Hz,1H),7.09(d,J＝7.3Hz,1H),6.84(s,1H),4.97(d,J＝6.0Hz,1H),4.40(d,J＝14.1Hz,1H),4.02(d,J＝14.4Hz,1H),3.91(d,J＝14.4Hz,1H),3.75(d,J＝14.1Hz,1H),2.96(d,J＝14.2Hz,1H),2.91(d,J＝14.1Hz,1H),2.51(s,1H),2.46(s,3H),1.90(dd,J＝11.6,6.0Hz,1H),1.13(d,J＝11.7Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.4,136.6,135.3,134.9,134.1,133.2,132.3,131.5,129.7,127.9,127.9,127.8,127.6,127.5,127.3,126.7,126.6,126.2,126.0,124.9,122.1,75.5,64.8,58.4,48.5,33.5,30.3,26.3,26.2,21.5.
example 6
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2f (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 11/1, V/V) to give the objective product 1f (56 mg, white solid, yield 58%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.73(d,J＝8.2Hz,2H),7.31(d,J＝7.9Hz,2H),7.27–7.24(m,1H),7.21(d,J＝7.1Hz,1H),7.16(td,J＝7.4,1.2Hz,1H),7.09(d,J＝7.2Hz,1H),5.53(t,J＝7.3Hz,1H),4.93(d,J＝6.0Hz,1H),3.97(d,J＝13.7Hz,1H),3.91(s,1H),3.74(d,J＝14.6Hz,1H),3.67(d,J＝13.7Hz,1H),2.72(d,J＝14.1Hz,1H),2.48(d,J＝14.1Hz,1H),2.44(s,3H),2.34(s,1H),2.07–1.97(m,2H),1.88(dd,J＝11.4,6.0Hz,1H),1.36–1.26(m,8H),1.17(d,J＝11.5Hz,1H),0.89(t,J＝7.0Hz,3H)； 13 C NMR(150MHz,CDCl 3 )δ143.2,136.6,135.3,132.6,132.3,131.3,129.5,127.6,127.4,126.6,124.8,122.1,75.4,65.0,58.3,48.3,33.1,31.7,29.5,29.4,29.0,28.1,27.1,25.9,22.6,21.5,14.1.
example 7
A10 mL round bottom flask was taken and charged with 2g (0.2 mmol) of o-alkynyl benzaldehyde in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 6/1, V/V) to give 1g (90 mg, white solid, yield 91%).
The reaction equation is:
1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝7.9Hz,2H),7.40(d,J＝7.3Hz,2H),7.34–7.31(m,4H),7.26–7.25(m,3H),7.18–7.15(m,1H),7.09(d,J＝7.1Hz,1H),6.95–6.88(m,1H),6.62(d,J＝15.4Hz,1H),6.27(d,J＝10.8Hz,1H),4.94(d,J＝5.7Hz,1H),4.13(d,J＝13.8Hz,1H),3.90–3.79(m,2H),3.76(d,J＝14.2Hz,1H),3.01(d,J＝14.1Hz,1H),2.66(d,J＝14.1Hz,1H),2.45(s,4H),1.97(dd,J＝10.9,5.9Hz,1H),1.26(d,J＝11.2Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ143.4,137.0,136.3,135.2,134.3,133.9,132.4,130.4,129.6,128.7,127.9,127.7,127.3,126.7,126.4,124.9,123.6,122.1,75.5,64.8,58.2,48.3,32.8,29.9,27.4,26.2,21.5.
the single crystal diffraction pattern of the target product 1g is shown in FIG. 4.
Example 8
A10 mL round bottom flask was taken and was charged with o-alkynyl benzaldehyde for 2h (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 11/1, V/V) to give the objective product (78 mg, white solid, yield 80%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.73(d,J＝7.9Hz,2H),7.37(s,2H),7.33(d,J＝7.7Hz,2H),7.28–7.25(m,5H),7.16(t,J＝6.7Hz,1H),7.08(d,J＝6.7Hz,1H),5.75(s,1H),4.94(d,J＝5.5Hz,1H),4.17(d,J＝14.4Hz,1H),3.88(d,J＝14.4Hz,1H),3.79(d,J＝14.4Hz,1H),3.74(d,J＝14.4Hz,1H),3.28(d,J＝13.7Hz,1H),2.62(d,J＝13.7Hz,1H),2.53(s,1H),2.44(s,3H),2.17(dd,J＝11.2,5.7Hz,1H),1.26(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ146.2,143.6,135.9,135.2,132.4,131.3,129.7,128.3,127.8,127.3,126.8,124.9,122.9,122.1,109.9,93.9,85.9,75.6,64.4,56.6,48.4,32.8,32.1,28.0,25.8,21.5.
example 9
A10 mL round bottom flask was taken and the drug molecule probenecid-derived o-alkynyl benzaldehyde 2i (0.2 mmol) was added sequentially,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=6/1 to 4/1, V/V) to give the objective product 1i (90 mg, white solid, yield 77%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.74–7.72(m,4H),7.32(d,J＝8.0Hz,4H),7.27–7.25(m,1H),7.20–7.16(m,2H),7.09(d,J＝7.3Hz,1H),6.70(s,1H),4.97(d,J＝5.9Hz,1H),4.37(d,J＝14.3Hz,1H),4.03(d,J＝14.3Hz,1H),3.79(d,J＝14.3Hz,1H),3.62(d,J＝14.3Hz,1H),3.07(dd,J＝8.7,6.3Hz,4H),2.86(d,J＝14.2Hz,1H),2.83(d,J＝14.2Hz,1H),2.45(s,1H),2.44(s,3H),1.87(dd,J＝11.6,6.0Hz,1H),1.57–1.50(m,4H),1.14(d,J＝11.6Hz,1H),0.85(t,J＝7.4Hz,6H)； 13 C NMR(150MHz,CDCl 3 )δ143.5,140.6,138.7,137.2,136.4,135.2,132.1,129.9,129.7,128.9,127.8,127.2,127.1,126.7,125.1,75.5,64.6,58.1,49.9,48.4,33.5,30.3,26.0,25.9,21.9,21.5,11.1.
example 10
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2j (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 (0.01 mmol) and dichloroethane (4 mL) are added under argon atmosphere, the reaction is carried out for 12 hours at 60 ℃, the reaction is cooled to room temperature after the completion, molecular sieve is removed by filtration, the solvent is removed by rotary evaporation and concentration of filtrate, and crude product is separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate=20/1-11/1, V/V) to obtain target product 1j (64 mg, white solid, yield 65))。
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.34–7.30(m,4H),7.24(t,J＝7.4Hz,1H),7.20(d,J＝7.4Hz,2H),7.19–7.16(m,1H),6.97(d,J＝7.5Hz,1H),6.87(t,J＝8.7Hz,1H),6.70(s,1H),5.38(d,J＝6.0Hz,1H),4.35(d,J＝14.1Hz,1H),4.00(d,J＝14.4Hz,1H),3.83(d,J＝14.4Hz,1H),3.65(d,J＝14.1Hz,1H),2.88(d,J＝14.1Hz,1H),2.85(d,J＝14.1Hz,1H),2.49(s,1H),2.45(s,3H),1.88(dd,J＝11.7,6.1Hz,1H),1.15(d,J＝11.8Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ156.1(d,J＝245.8Hz),143.5,136.5,135.5(d,J＝5.7Hz),134.2,131.7,129.7,128.7(d,J＝8.0Hz),128.5,128.4,127.3,127.2,122.4(d,J＝3.0Hz),121.9(d,J＝18.3Hz),111.8(d,J＝21.0Hz),68.6,65.0,58.4,48.2,32.9,30.0,26.4,25.8,21.5； 19 F NMR(565MHz,CDCl 3 )δ-126.59–-126.67(m).
example 11
A10 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2k (0.2 mmol) in sequence,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 9/1, V/V) to give the objective product 1k (98 mg, white solid, yield 92%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.75(d,J＝8.3Hz,2H),7.51(dd,J＝7.8,1.0Hz,1H),7.34–7.29(m,6H),7.25–7.23(m,1H),7.20(d,J＝7.4Hz,2H),6.72(s,1H),5.01(d,J＝6.0Hz,1H),4.37(d,J＝14.1Hz,1H),4.02(d,J＝14.4Hz,1H),3.81(d,J＝14.4Hz,1H),3.64(d,J＝14.1Hz,1H),2.89(s,2H),2.56(s,1H),2.46(s,3H),1.93(dd,J＝11.8,6.0Hz,1H),1.14(d,J＝11.8Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.5,136.7,136.5(d,J＝2.1Hz),135.5,134.1,131.9,129.8,128.5,128.4,127.3,127.2,127.2,127.1,127.0,125.3,124.75(d,J＝3.8Hz),119.1(d,J＝3.8Hz),75.1,65.4,58.5,48.1,33.1,29.9,26.8,26.0,21.5； 19 F NMR(565MHz,CDCl 3 )δ-61.84.
example 12
A10 mL round bottom flask was taken and charged with 2L (0.2 mmol) of o-alkynyl benzaldehyde,
Molecular sieves (200 mg), SIMesaAuNTf 2 Dichloroethane (4 mL) was added (0.01 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, the molecular sieve was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=15/1 to 9/1, V/V) to give 1l of the objective product (66 mg, white solid, yield 69%).
The reaction equation is:
1 H NMR(600MHz,CDCl 3 )δ7.76(d,J＝8.2Hz,2H),7.33–7.30(m,4H),7.23(t,J＝7.5Hz,1H),7.21(d,J＝7.4Hz,2H),6.99–6.97(m,3H),6.70(s,1H),4.93(d,J＝5.9Hz,1H),4.36(d,J＝14.1Hz,1H),4.00(d,J＝14.3Hz,1H),3.84(d,J＝14.3Hz,1H),3.64(d,J＝14.1Hz,1H),2.88(d,J＝14.1Hz,1H),2.82(d,J＝14.1Hz,1H),2.46(s,3H),2.38(s,1H),2.34(s,3H),1.87(dd,J＝11.5,6.0Hz,1H),1.15(d,J＝11.6Hz,1H)； 13 C NMR(150MHz,CDCl 3 )δ143.3,137.5,136.7,136.6,134.5,132.6,132.4,131.7,129.7,128.5,128.4,127.4,127.3,127.1,125.5,121.9,77.2,77.0,76.8,75.3,64.7,58.5,48.4,33.9,30.3,26.2,25.8,21.5,21.4.
example 13
In order to verify the industrial application of the invention, gram-scale amplification experiments are also carried out, when the raw material o-alkynyl benzaldehyde 2a is amplified to 2.3mmol (1.06 g), the expected product can be obtained in 70% yield when the gold catalyst loading is 5mol%, and the invention is fully shown to be applicable to industrial application.
A100 mL round bottom flask was taken and charged with O-alkynyl benzaldehyde 2a (2.3 mmol,1.06 g),
Molecular sieves (2.3 g), SIMesaAuNTf 2 Dichloroethane (46 mL) was added (0.115 mmol) under argon atmosphere, the reaction was carried out at 60℃for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature, molecular sieves were removed by filtration, the solvent was removed by rotary evaporation of the filtrate, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 11/1, V/V) to give the objective product 1a (0.74 g, white solid, yield 70%).
The reaction equation is:
example 14
Examples 1-13 the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compounds as intermediates can be further structurally modified and chemically converted to various compounds. The present example performs the following experiments:
a10 mL round bottom flask was taken and cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound 1a (0.2 mmol) was dissolved in ethyl acetate (4 mL) and Pd/C (9.4 mg,10 wt%) was added under argon. The reaction was then carried out at room temperature under hydrogen atmosphere for 12h (thin layer chromatography followed by reaction until completion), after completion of the reaction, celite was filtered, the solvent was removed by rotary evaporation, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20/1 to 11/1, V/V) to give reduced rearrangement product 3 (25.4 mg, white solid, yield 27%) and diastereoisomer 3' (44.6 mg, white solid, yield 47%).
The target product 3 was characterized.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.3Hz,2H),7.30–7.27(m,4H),7.24–7.20(m,1H),7.16–7.13(m,1H),7.12–7.09(m,4H),7.02–7.00(m,1H),4.08(dd,J＝16.2,1.5Hz,1H),3.75(d,J＝16.0Hz,1H),3.57(d,J＝11.4Hz,1H),3.49(d,J＝16.2Hz,1H),2.91–2.84(m,1H),2.80–2.72(m,2H),2.60–2.54(m,1H),2.47–2.37(m,6H),2.26–2.19(m,1H),1.70–1.64(m,2H),1.40–1.34(m,1H)； 13 C NMR(150MHz,CDCl 3 )δ209.7,143.8,138.6,135.3,134.7,134.0,129.9,129.6,128.9,128.6,128.5,127.0,126.4,126.2,125.8,58.2,53.6,50.8,42.6,40.5,38.3,35.2,32.4,25.7,21.5.
The target product 3' is characterized.
1 H NMR(400MHz,CDCl 3 )δ7.54(d,J＝8.3Hz,2H),7.28(dd,J＝7.4,5.9Hz,4H),7.34–7.20(m,1H),7.13–7.11(m,2H),7.10–7.07(m,3H),7.02–7.00(m,1H),4.45(dd,J＝17.3,1.7Hz,1H),3.70(d,J＝14.0Hz,1H),3.51(d,J＝17.3Hz,1H),3.24(d,J＝16.4Hz,1H),2.80–2.76(m,2H),2.55(s,1H),2.51(s,3H),2.43(s,3H),2.40–2.35(m,1H),2.33–2.25(m,2H),1.82(d,J＝14.7Hz,1H),1.30–1.23(m,2H). 13 C NMR(150MHz,CDCl 3 )δ209.9,143.8,138.6,134.9,134.7,129.9,129.3,128.9,128.5,128.4,126.9,126.5,125.8,125.8,58.7,54.4,50.7,40.4,39.1,38.3,27.0,25.9,21.5.
It can be seen that the cyclopropane fused 6/7/7 benzoxy bridged polycyclic compound 1a prepared in example 13 can be subjected to Pd/C reduction rearrangement to obtain spiro compound 3 and diastereoisomer 3' thereof, and the reaction equation is as follows:
example 15
On the basis of example 1, the reaction conditions such as gold catalyst, solvent, reaction temperature, reaction time were optimized, and the specific optimization results are shown in the following table 1:
TABLE 1
| Catalyst (5 mol%) | Solvent (0.05M) | Temperature (. Degree. C.) | Time (h) | Yield (%) | |
| 1 | JohnPhosAuNTf 2 | Toluene (toluene) | 60 | 12 | 22 |
| 2 | XPhosAuNTf 2 | Toluene (toluene) | 60 | 12 | 24 |
| 3 | IPrAuNTf 2 | Toluene (toluene) | 60 | 12 | 61 |
| 4 | IMesAuNTf 2 | Toluene (toluene) | 60 | 12 | 70 |
| 5 | SIPrAuNTf 2 | Toluene (toluene) | 60 | 12 | 45 |
| 6 | SIMesAuNTf 2 | Toluene (toluene) | 60 | 12 | 75 |
| 7 | SIMesAuNTf 2 | Dichloroethane (dichloroethane) | 60 | 12 | 81 |
| 8 | SIMesAuNTf 2 | Methyl tert- |
60 | 12 | 52 |
| 9 | SIMesAuNTf 2 | Dichloroethane (dichloroethane) | rt | 16 | 79 |
| 10 | SIMesAuNTf 2 | Dichloroethane (dichloroethane) | 80 | 12 | 81 |
As can be seen from the data in Table 1, SIMESAuNTf was used under the same reaction conditions 2 As catalyst, the yields are highest, other catalysts are used, such as the phosphine ligand catalyst JohnPhosphauNTf 2 、XPhosAuNTf 2 And carbene catalyst IPrAuNTf 2 、IMesAuNTf 2 、SIPrAuNTf 2 When the time is equal, the product yield is reduced to different degrees. Under the same reaction conditions, the yield was highest when the solvent was changed to dichloroethane, and the yield was lowered when the solvent was methyl t-butyl ether.
By SIMesaAuNTf 2 As a catalyst, the reaction temperature is 60 ℃ for 12 hours, and the yield is up to 81%; the reaction time needs to be prolonged to 16 hours when the temperature is room temperature; while the temperature increased to 80 c had little effect on the yield.
The invention takes simple and easily obtained o-alkynyl benzaldehyde compounds as raw materials and SIMESAuNTf 2 、JohnPhosAuNTf 2 、XPhosAuNTf 2 、IPrAuNTf 2 、IMesAuNTf 2 、SIPrAuNTf 2 And the catalyst is gold catalysis [3+2 ]]Construction of tandem cyclization strategy is not conventionalThe cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound is easy to prepare, and four continuous chiral centers can be constructed in one step. The method has the advantages of easily available raw materials, simple operation, mild conditions, wide range of reaction substrates, high yield and the like.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.
Claims (6)
1. A method for synthesizing cyclopropane fused 6/7/7 benzoxy bridge polycyclic compounds is characterized in that: heating a compound shown in a formula (II) serving as a raw material in a solvent under the catalysis of a gold catalyst to obtain the compound shown in the formula (I);
wherein R is 1 One selected from phenyl, halogen substituted phenyl, trifluoromethyl substituted phenyl, sulfonamide substituted phenyl, C1-C3 alkyl substituted phenyl, naphthyl, C1-C6 alkyl, styryl or phenylethynyl; r is R 2 One selected from hydrogen, halogen, methyl, trifluoromethyl, methoxy and cyano;
the gold catalyst is selected from one of catalysts shown in formulas (V) - (VIII);
the solvent is selected from one of toluene, dichloroethane and methyl tertiary butyl ether;
the heating reaction in the solvent also comprises the steps of adding into a reaction system
Molecular sieves.
2. The method for synthesizing the cyclopropane-fused 6/7/7-benzoxy-bridged polycyclic compound as recited in claim 1, wherein: the molar ratio of the gold catalyst to the compound shown in the formula (II) is 0.03-0.1:1.
3. The method for synthesizing the cyclopropane-fused 6/7/7-benzoxy-bridged polycyclic compound as recited in claim 1, wherein: the solvent is dichloroethane.
4. A method for synthesizing a cyclopropane-fused 6/7/7-benzoxycyclic compound according to any one of claims 1 to 3, wherein: the concentration of the compound shown in the formula (II) in the solvent is 0.05-0.2 mol/L.
5. A method for synthesizing a cyclopropane-fused 6/7/7-benzoxycyclic compound according to any one of claims 1 to 3, wherein: the said
The molecular sieve is added in an amount of 50-200 mg per 0.1mmol of the compound represented by the formula (II).
6. A method for synthesizing a cyclopropane-fused 6/7/7-benzoxycyclic compound according to any one of claims 1 to 3, wherein: the reaction temperature is 25-80 ℃ and the reaction time is 12-24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210854077.XA CN115232139B (en) | 2022-07-13 | 2022-07-13 | Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210854077.XA CN115232139B (en) | 2022-07-13 | 2022-07-13 | Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115232139A CN115232139A (en) | 2022-10-25 |
| CN115232139B true CN115232139B (en) | 2023-06-20 |
Family
ID=83673443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210854077.XA Active CN115232139B (en) | 2022-07-13 | 2022-07-13 | Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115232139B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115197232A (en) * | 2022-07-13 | 2022-10-18 | 南京林业大学 | Cyclopropane fused oxygen bridge hexacyclic compound and synthesis method thereof |
-
2022
- 2022-07-13 CN CN202210854077.XA patent/CN115232139B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN115232139A (en) | 2022-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hoashi et al. | Enantioselective tandem Michael reaction to nitroalkene catalyzed by bifunctional thiourea: total synthesis of (−)-epibatidine | |
| Tiso et al. | Organocatalysts and sequential asymmetric cascade reactions in the synthesis of functionalized isoindolinones and benzoindolizidinones | |
| JP2004538276A (en) | Manufacturing method of escitalopram | |
| CN101157655A (en) | Method for synthesizing (4S,5R)- half-ester | |
| CN114591277B (en) | 5/6/7/6 tetracyclic compound fused with benzene ring and synthetic method thereof | |
| CN107056795B (en) | A kind of loop coil hydroxyindole pentamethylene and β-lactones compound synthesis method | |
| CN114437103B (en) | Method for synthesizing chiral tetrahydrobenzoxepin compound through gold-catalyzed asymmetric cycloaddition reaction | |
| Proessdorf et al. | Concise Total Synthesis of (+)-Atlanticone C | |
| Davies et al. | Application of the combined C–H activation/Cope rearrangement as a key step in the total syntheses of the assigned structure of (+)-elisabethadione and a (+)-p-benzoquinone natural product | |
| CN115232139B (en) | Cyclopropane fused 6/7/7 benzoxy bridge polycyclic compound and synthetic method thereof | |
| CN102766092A (en) | Method for synthesizing optically active tetrahydroquinoline derivative in presence of chiral spiro phosphoric acid serving as catalyst | |
| CN115197232A (en) | Cyclopropane fused oxygen bridge hexacyclic compound and synthesis method thereof | |
| EP1731509B1 (en) | Process for producing nitrogenous 5-membered cyclic compound | |
| Yang et al. | Highly diastereo-and enantioselective organocatalytic addition of acetone to β-substituted α-ketoesters via dynamic kinetic resolution | |
| Sun et al. | Highly diastereoselective and enantioselective addition of organometallic reagents to a chiral C2-symmetrical bisimine | |
| CN115626895B (en) | Biaryl bridged eight-membered or nine-membered or ten-membered nitrogen-containing heterocyclic compound and synthesis method thereof | |
| JP2001526111A (en) | Catalyst compositions based on chiral ligands having molybdenum, tungsten or chromium and methods for asymmetric alkylation of allylic substrates | |
| CN108250206B (en) | Synthetic method of biaryllignans compound and intermediate thereof | |
| AU2004276354B2 (en) | Resolution of a narwedine amide derivative | |
| JP3716460B2 (en) | Asymmetric cyclopropanation reaction | |
| El Abed et al. | Synthesis of a configurationally locked [5] helicene derivative | |
| US20050215832A1 (en) | Process for producing optically active nitroalcohols | |
| CN110790708A (en) | Preparation method of Ailixipine intermediate | |
| Yanagisawa et al. | Chiral Silver Alkoxide Catalyzed Asymmetric Aldol Reaction of Alkenyl Esters with Isatins | |
| CN115010649B (en) | C-N axis chiral benzo [ C ] carbazole compound and synthesis method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |