A method for organocatalytic synthesis of axially chiral arylindole

A technology of aryl indole and axial chirality, which is applied in the field of organocatalytic synthesis of axial chiral aryl indole, achieving the effects of mild reaction conditions, excellent enantioselectivity, and good yield

Active Publication Date: 2020-01-10
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In stark contrast, the enantioselective synthesis of axially chiral arylindoles still faces great challenges

Method used

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  • A method for organocatalytic synthesis of axially chiral arylindole
  • A method for organocatalytic synthesis of axially chiral arylindole
  • A method for organocatalytic synthesis of axially chiral arylindole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Synthesis of Substrate 1

[0057]

[0058] Aryl ring substituted β-naphthylamine 1i-aaa (R 5 =6-Me), 1k-aaa(R 5 =6-Ph), 1l-aaa(R 5 =7-MeO), other β-naphthylamines are commercially available.

[0059] first step:

[0060] According to reference 3, in an ice-water bath, the NaNO 2 (513 mg, 5.76 mmol) of H 2 A solution of O (1 mL) was slowly added to a suspension of the corresponding amine (4.5 mmol) in HCl (5 mL), the resulting solution was stirred in an ice-water bath for 1 h, and SnCl was added slowly 2 2H 2 O (3.556 g, 15.76 mol), the resulting suspension was stirred in an ice-water bath for 3.5 hours, then filtered. sequentially at 0°C with H 2 O (4×8mL), use H at room temperature 2 O (1×8mL), Et 2 The solid was washed with O / n-hexane (1:1, 2×4 mL), and the desired product was obtained after the solid was dried.

[0061]

[0062] Following the general method, 1i-aa was obtained in 96% yield.

[0063] 1 H NMR (400MHz, DMSO-d 6 )δ10.46(s,3H),8.48(s,1...

Embodiment 2

[0103] Synthesis of Substrate 2

[0104]

[0105] 2a, 2i can be purchased commercially, and other indoles were prepared according to references 6-10.

[0106] General method for the synthesis of 2-(tert-butyl)-1H-indole

[0107]

[0108] The corresponding phenylhydrazine hydrochloride (0.72g, 5mmol) and pinacolone (5mL, 40mmol), ZnCl 2 (2.72g, 20mmol) were mixed, and heated at 190° C. with an oil bath, and the reaction mixture was maintained at this temperature for 20 minutes. After the completion of the reaction monitored by TLC, the reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (2 × 50 mL), the combined organic phases were washed with water and washed with Na 2 SO 4 After drying and evaporation of the solvent, the residue was purified by column chromatography on silica gel using PE / EA as eluting solvent to give the product.

[0109] 2b, yellow solid, 77% yield, 0.73g.

[0110] 1 H NMR (500MHz, CDCl 3 )δ7.91...

Embodiment 3

[0119] In order to verify the feasibility of the reaction, as shown in the following formula, azobenzene derivative 1a and 2-tert-butyl-indole 2a were used as reactants, and 10mol% phosphoric acid CP1 was used as a catalyst to react in DCM at room temperature. The reaction proceeded smoothly, and the axial chiral arylindole 3a was obtained with a yield of 76% and an ee value of 87%. It can be seen that the asymmetric construction of axial chiral arylindole by organocatalysis is feasible through the nucleophilic attack of azobenzene derivatives by indole. Next, catalysts with different axial chiral skeletons and substituents were screened. The aromatic ring skeleton and 3,3'-substituents of the catalysts had a significant impact on enantioselectivity. Among them, catalyst CP4 had the best results in terms of enantioselectivity (92% ee) and yield (99%).

[0120]

[0121] Reaction conditions: 1a (0.10mmol, 1.0eq), 2a (0.12mmol, 1.2eq) and CP (10mol%) were reacted in dichlorom...

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Abstract

The invention discloses a method for synthetizing axial chirality aryl indole through organocatalysis. The method is characterized in that chiral phosphoric acid is used as a catalyst; a compound 1 and a compound 2 react: the chemical formula is shown as the description, wherein R<1> is hydrogen; R<2> is selected from tertiary butyl, 1-methyl cyclopropyl, 1-methyl cyclobutyl, tertiary pentyl, aryl and heteroaryl; R<3> represents any substituent group; n represents an integer being 1 to 4, and when n is greater than 2, existent two or greater R<3> are identical or different; R<4> selects CO2R, and R is alkyl or benzyl; R<5> represents any substituent group; m represents an integer being 1 to 4, and when m is greater than 2, existent two or greater R<5> are identical or different. The synthesis method is applicable to azobenzene derivatives of various kinds of ester; the axial chirality aryl indole is obtained at good yield and excellent enantioselectivity; the reaction conditions are mild. The method opens up a novel path for organocatalysis of asymmetrical aromatic functionalization.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a method for synthesizing axial chiral arylindole by organic catalysis. Background technique [0002] Arylation is a fundamental reaction in organic chemistry, mainly achieved by electrophilic substitution of aryl groups or transition metal-catalyzed functionalization of aryl groups. In aryl electrophilic substitution, the aromatic ring acts as a nucleophile, and many important transformations such as aromatic nitration, halogenation, sulfonation, acylation, and alkylation can be carried out by aryl electrophilic substitution. Aryl nucleophilic substitution involving aryl C–H cleavage has been relatively poorly studied. In the past decade, aromatic rings have been used as electrophiles to react with different nucleophiles in many useful transformations (such as transition metal-catalyzed C–H activation of aryl groups), but organocatalytic arylation involving nucleophilic substit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/14
CPCC07D209/14
Inventor 谭斌漆良文毛建辉
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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