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CN-121974851-A - Method for photocatalytic asymmetric intermolecular dearomatization cycloaddition reaction based on naphthalene derivative

CN121974851ACN 121974851 ACN121974851 ACN 121974851ACN-121974851-A

Abstract

The invention provides a method for performing dearomatization cycloaddition reaction between asymmetric molecules based on a naphthalene derivative, belonging to the technical field of chemical synthesis. The invention takes olefin compounds and 2-pyrazole amide naphthalene derivatives as reaction raw materials, and realizes [2+2] -cycloaddition or [4+2] -cycloaddition reaction under specific reaction conditions, and the obtained product has high yield and high enantioselectivity. The substrate disclosed by the invention has good universality, is especially suitable for naphthalene-containing raw materials, overcomes the problem that naphthalene-containing compounds are difficult to react in the prior art, and has good application prospects.

Inventors

  • LIU XIAOHUA
  • TANG SHI
  • FENG XIAOMING
  • Dong Shunxi
  • CAO WEIDI
  • ZHOU YUQIAO

Assignees

  • 四川大学

Dates

Publication Date
20260505
Application Date
20260126

Claims (10)

  1. 1. A compound of formula IA: IA (IA) Wherein, the The ring A is selected from 5-6 membered heterocycloalkyl, 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and phenyl, wherein the heteroatom of the heterocycloalkyl is N, and the number of the heteroatom is 1; n is selected from 0, 1, 2 or 3; R is selected from 2, 6-dimethylbenzene, 2, 6-diethylbenzene, 2, 6-diisopropylbenzene, 2, 6-diethyl-4-bromobenzene, 2, 6-diethyl-4-methoxybenzene, 2, 6-diethyl-trityl benzene, 2, 6-diisopropyl-4-dinaphthyl benzene and 2, 6-diisopropyl-4-benzhydryl benzene.
  2. 2. The compound or salt thereof according to claim 1, wherein the compound is represented by formula IA-1: IA-1 Wherein R is selected from 2, 6-dimethylbenzene, 2, 6-diethylbenzene, 2, 6-diisopropylbenzene, 2, 6-diethyl-4-bromobenzene, 2, 6-diethyl-4-methoxybenzene, 2, 6-diethyl-trityl benzene, 2, 6-diisopropyl-4-dinaphthyl benzene and 2, 6-diisopropyl-4-benzhydryl benzene; Or the compound is shown as formula IA-2, formula IA-3, formula IA-4 or formula IA-5: Formula IA-2 formula IA-3 formula IA-4 formula IA-5 Wherein R is selected from 2, 6-diisopropylbenzene; preferably, the compound is 。
  3. 3. Use of a compound according to claim 1 or 2 or a salt thereof for the photocatalytic asymmetric intermolecular dearomatization cycloaddition reaction of naphthalene derivatives with olefinic compounds; preferably, the photocatalytic asymmetric intermolecular dearomatization cycloaddition reaction is a photocatalytic asymmetric intermolecular dearomatization [2+2] -cycloaddition reaction and/or a photocatalytic asymmetric intermolecular dearomatization [4+2] -cycloaddition reaction.
  4. 4. A method for catalyzing asymmetric intermolecular dearomatization [2+2] -cycloaddition reaction based on naphthalene derivatives is characterized by comprising the following steps: in a solvent, a naphthalene derivative shown in a formula IA, an alkene compound shown in a formula IIA and a coordination additive are subjected to asymmetric catalytic reaction by illumination under the catalysis of a chiral diazoxide ligand and a metal compound, so that a compound shown in a formula III is obtained; Wherein, the A is the number of substituent R 1 at any position on the benzene ring, and a is selected from 0, 1,2, 3 or 4; Each R 1 is independently selected from C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, halogen, OR-C (O) OR 6 ; R 2 is selected from C 1 ~C 6 alkoxy or halogen; b is the number of substituents R 3 at any position on the benzene ring, b is selected from 0, 1,2, 3 or 4; Each R 3 is independently selected from cyano, substituted or unsubstituted C 1 ~C 6 alkyl, halogen, C 1 ~C 6 alkoxy, trimethylsilyl, -C (O) R 7 、-C(O)OR 8 , or-OC (O) R 8 , the substituents of the alkyl groups being selected from halogen; R 6 is selected from C 1 ~C 6 alkyl; R 7 is selected from phenyl; r 8 is selected from C 1 ~C 6 alkyl; r 4 、R 5 is independently selected from hydrogen, C 1 ~C 6 alkyl, or R 4 and R 5 form = R 9 ; R 9 is selected from O or CH 2 .
  5. 5. The method according to claim 4, wherein: the molar ratio of the naphthalene derivative shown in the formula IA to the alkene compound shown in the formula IIA is 1 (1-10); And/or the molar ratio of the metal compound to the chiral dinitrogen oxygen ligand is 1 (1-2); and/or, the molar ratio of the naphthalene derivative shown in the formula IA to the metal compound is 1 (0.1-0.5); And/or, the mol ratio of the naphthalene derivative shown in the formula IA to the coordination additive is 1 (0.1-0.5); And/or the molar volume ratio of the naphthalene derivative shown in the formula IA to the solvent is 1mmol (10-100 mL); and/or the reaction temperature is 0 to-80 ℃, and the reaction time is 1-10 hours; and/or the illumination wavelength of the reaction is 400-500 nm, and the illumination power is 10-20W; Preferably, the method comprises the steps of, The molar ratio of the naphthalene derivative shown in the formula IA to the alkene compound shown in the formula IIA is 1:10; and/or the molar ratio of the metal compound to the chiral dinitrogen oxygen ligand is 1:1.5; and/or, the molar ratio of the naphthalene derivative shown in the formula IA to the metal compound is 1:0.1; And/or, the molar ratio of naphthalene derivative of formula IA to complexing additive is 1:0.5; and/or the reaction temperature is-78 to-80 ℃, and the reaction time is 2-8 hours; and/or the illumination wavelength of the reaction is 400nm, and the illumination power is 10W.
  6. 6. The method according to claim 4, wherein: the coordination additive is benzoic acid; and/or, the chiral diazoxide ligand according to claim 1 or 2; and/or the metal compound is selected from Tb(OTf) 3 、Sc(OTf) 3 、Mg(OTf) 2 、Ni(OTf) 2 、Gd(OTf) 3 、Eu(OTf) 3 or Dy (OTf) 3 ; And/or the solvent is selected from dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethyl acetate, acetonitrile or methanol; Preferably, the method comprises the steps of, The chiral diazoxide ligand is ; And/or the metal compound is selected from Tb (OTf) 3 ; And/or the solvent is selected from toluene.
  7. 7. A method for catalyzing asymmetric intermolecular dearomatization [4+2] -cycloaddition reaction based on naphthalene derivatives is characterized by comprising the following steps: In a solvent, a naphthalene derivative shown in a formula IB, an alkene compound shown in a formula IIB and a coordination additive are subjected to asymmetric catalytic reaction by illumination under the catalysis of a chiral dinitrogen oxygen ligand and a metal compound, so that a compound shown in a formula exo-IV and/or endo-IV is obtained; Wherein, the A is the number of substituent R 1 at any position on the benzene ring, and a is selected from 0, 1,2, 3 or 4; Each R 1 is independently selected from C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, halogen, OR-C (O) OR 6 ; R 6 is selected from C 1 ~C 6 alkyl; R 2' is selected from OR-OR 10 ; R 2 is selected from C 1 ~C 6 alkoxy or halogen; R 10 is selected from C 1 ~C 6 alkyl; R 3' is selected from cyano, -C (O) OR 11 , 、 、 、 、 、 、 ; R 11 is selected from C 1 ~C 6 alkyl; b is the number of substituents R 3 at any position on the ring, b is selected from 0, 1,2, 3 or 4; Each R 3 is independently selected from cyano, substituted or unsubstituted C 1 ~C 6 alkyl, halogen, C 1 ~C 6 alkoxy, trimethylsilyl, -C (O) R 7 、-C(O)OR 8 , or-OC (O) R 8 , the substituents of the alkyl groups being selected from halogen; R 7 is selected from phenyl; r 8 is selected from C 1 ~C 6 alkyl; R 4 、R 5 is independently selected from hydrogen, C 1 ~C 6 alkyl.
  8. 8. The method according to claim 7, wherein: The molar ratio of the naphthalene derivative shown in the formula IB to the alkene compound shown in the formula IIB is 1 (1-5); And/or the molar ratio of the metal compound to the chiral dinitrogen oxygen ligand is 1 (1-2); and/or the molar ratio of the naphthalene derivative shown in the formula IB to the metal compound is 1 (0.1-0.5); and/or the molar ratio of the naphthalene derivative shown in the formula IB to the coordination additive is 1 (0.1-0.5); And/or the molar volume ratio of the naphthalene derivative shown in the formula IB to the solvent is 1mmol (10-100 mL); And/or the reaction temperature is 0 to-80 ℃, and the reaction time is 1 to 50 hours; and/or the illumination wavelength of the reaction is 400-500 nm, and the illumination power is 10-20W; Preferably, the method comprises the steps of, The molar ratio of the naphthalene derivative shown in the formula IB to the alkene compound shown in the formula IIB is 1:1; and/or the molar ratio of the metal compound to the chiral dinitrogen oxygen ligand is 1:1.5; and/or, the molar ratio of naphthalene derivative to metal compound of formula IB is 1:0.1; And/or, the molar ratio of naphthalene derivative of formula IB to complexing additive is 1:0.5; And/or the reaction temperature is-20 to-50 ℃, and the reaction time is 24-48 hours; and/or the illumination wavelength of the reaction is 400nm, and the illumination power is 10W.
  9. 9. The method according to claim 7, wherein: the coordination additive is benzoic acid; and/or, the chiral diazoxide ligand according to claim 1 or 2; and/or the metal compound is selected from Tb(OTf) 3 、Sc(OTf) 3 、Mg(OTf) 2 、Ni(OTf) 2 、Gd(OTf) 3 、Eu(OTf) 3 or Dy (OTf) 3 ; And/or the solvent is selected from dichloromethane, tetrahydrofuran, toluene, diethyl ether, ethyl acetate, acetonitrile or methanol; Preferably, the method comprises the steps of, The chiral diazoxide ligand is ; And/or the metal compound is selected from Tb (OTf); and/or the solvent is selected from dichloromethane.
  10. 10. The compound prepared by the method of any one of claims 4-9, which is characterized in that the compound is selected from one of the following structures: 。

Description

Method for photocatalytic asymmetric intermolecular dearomatization cycloaddition reaction based on naphthalene derivative Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for performing dearomatization cycloaddition reaction between asymmetric molecules based on photocatalysis of naphthalene derivatives. Background Chiral polycyclic structures are widely found in natural products and drug candidates, and Catalytic Asymmetric Dearomatization (CADA) reactions are efficient strategies for rapidly constructing such chiral backbones, which have been successfully applied to the conversion of various (hetero) aromatic hydrocarbons such as indoles, benzofurans, and the like. Naphthalene is a full-carbon aromatic hydrocarbon consisting of two fused benzene rings, pi electron conjugated systems are highly delocalized (10 pi electrons accord with the shock rule), molecular planarity is strong, and aromatic stabilization energy (aromatic stabilization energy, ASE) is significantly higher than that of most heterocyclic compounds. The strong stability makes the aromatic property of the heterocyclic compound to be destroyed, and the heterocyclic compound (such as indole, benzofuran, pyridine and the like) can destroy the integrity of a conjugated system due to the fact that hetero atoms (N, O, S) are introduced into the ring, the electronegativity of the hetero atoms and the difference between the hetero atoms and the carbon atoms are large, pi electrons are insufficient in delocalization, the aromatic stabilization energy is reduced (for example, the ASE of indole is lower than that of naphthalene), the aromatic property of partial heterocyclic ring (such as pyrrole and furan) is weak, and even the heterocyclic ring structure is 'partially aromatic', and the ring structure is more easy to be aromatic destroyed under the action of external energy (such as visible light and catalyst). It can be seen that naphthalene-containing aromatic hydrocarbons (non-heterocyclic aromatic compounds) are more difficult to dearomatize than heterocyclic compounds, and the core reasons are stronger aromatic stability, higher excitation energy requirements, and more significant thermodynamic and kinetic barriers to the reaction. The asymmetric dearomatization cycloaddition reaction of naphthalene has few reports, and the development of the reaction has important significance for enriching the synthesis method of chiral polycyclic compounds and meeting the requirements of the fields of pharmaceutical chemistry and the like on molecules with complex structures. Currently, few examples of intermolecular [2+2] -cycloaddition or [4+2] -cycloaddition reactions are achieved by photocatalytically substituting naphthalene derivative compounds with 2-pyrazole amides, and most of them are reported as racemates. Only two reports "Gd(III)-Catalyzed Regio‑, Diastereo‑, and Enantioselective [4+2] Photocycloaddition of Naphthalene Derivatives"(DOI: 10.1021/jacs.4c05288);"Enantioselective Dearomative [2π+2σ]Photocycloaddition of Naphthalene Derivatives with Bicyclo[1.1.0]butanes Enabled by Gd(III) Catalysis"(DOI: 10.1021/jacs.5c01506). of asymmetric synthesis of 1-pyridine substituted naphthalene derivatives are not reported, and the product can be obtained by carrying out [2+2] or [4+2] cycloaddition reaction between naphthalene derivatives. It is worth mentioning that the 2-naphthalene substituted [4+2] -cycloaddition product can be used for constructing similar structures of some drug molecules, can be used as calcium channel blocker and has the functions of vasodilation activity, myocardial ischemia resistance and the like （"Conformationally constrained calcium channel blockers: Novel mimics of 1-benzazepin-2-ones"(DOI: 10.1016/S0968-0896(00)82135-5)）. Therefore, a photocatalysis system which is simple and convenient to operate, efficient, green, controllable in cost and wide in substrate application range is developed, is used for realizing dearomatization cycloaddition reaction of 2-pyrazole amide substituted naphthalene derivative and olefin, and has important potential application value. Disclosure of Invention The invention aims to provide a method for catalyzing asymmetric intermolecular dearomatization cycloaddition reaction based on naphthalene derivatives. The present invention provides a compound represented by formula IA: IA (IA) Wherein, the The ring A is selected from 5-6 membered heterocycloalkyl, 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and phenyl, wherein the heteroatom of the heterocycloalkyl is N, and the number of the heteroatom is 1; n is selected from 0, 1, 2 or 3; R is selected from 2, 6-dimethylbenzene, 2, 6-diethylbenzene, 2, 6-diisopropylbenzene, 2, 6-diethyl-4-bromobenzene, 2, 6-diethyl-4-methoxybenzene, 2, 6-diethyl-trityl benzene, 2, 6-diisopropyl-4-dinaphthyl benzene and 2, 6-diisopropyl-4-benzhydryl benzene. Further, the compound is shown