CN111662274A - Method for synthesizing chiral hetero-triarylmethane - Google Patents

Method for synthesizing chiral hetero-triarylmethane Download PDF

Info

Publication number
CN111662274A
CN111662274A CN201910167900.8A CN201910167900A CN111662274A CN 111662274 A CN111662274 A CN 111662274A CN 201910167900 A CN201910167900 A CN 201910167900A CN 111662274 A CN111662274 A CN 111662274A
Authority
CN
China
Prior art keywords
chiral
substituent
reaction
hetero
indole
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.)
Pending
Application number
CN201910167900.8A
Other languages
Chinese (zh)
Inventor
周永贵
谢焕平
吴波
孙蕾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Institute of Chemical Physics of CAS
Original Assignee
Dalian Institute of Chemical Physics of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dalian Institute of Chemical Physics of CAS filed Critical Dalian Institute of Chemical Physics of CAS
Priority to CN201910167900.8A priority Critical patent/CN111662274A/en
Publication of CN111662274A publication Critical patent/CN111662274A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides a method for synthesizing a chiral hetero-triarylmethane compound, wherein a catalytic system used in the method is Bronsted acid. The reaction can be carried out under the following conditions, temperature: -20 ℃; solvent: mesitylene; the ratio of substrate to catalyst was 20/l. The bronsted acid catalyzes the addition reaction of the azediene derived from the aurone and the indole to obtain the corresponding heterotriarylmethane compound, and the enantiomeric excess of the compound can reach 99 percent. The method has the advantages of simple operation, high enantioselectivity, good yield, mild reaction conditions, good functional group tolerance, wide substrate application range and potential practical application value.

Description

Method for synthesizing chiral hetero-triarylmethane
Technical Field
The invention relates to a method for synthesizing chiral hetero-triarylmethane by asymmetric addition reaction, belonging to the field of asymmetric catalytic synthesis.
Background
Heterotriarylmethanes are widely found in pharmaceuticals and in biologically active molecules. The heterotriarylmethanes in the following figures have anti-inflammatory, anti-tuberculosis and anti-breast cancer drugs, respectively. (FIG. 1).
Figure BDA0001986936030000011
Because the hetero-triarylmethane has potential medicinal value and important application, the synthesis of chiral hetero-triarylmethane compound has important significance. The existing synthesis methods mainly comprise: (1) metal-catalyzed C-H bond activation; (2) metal catalyzed cross coupling reactions; (3) friedel-crafts alkylation reaction.
Although chiral hetero-triarylmethanes can be synthesized by various methods, most of the methods have been reported to be hetero-triarylmethanes containing heterocycles such as pyridine, indole, and benzothiophene, and few of the methods have been reported to be synthetic hetero-triarylmethanes containing benzofuran. Thus, the range of substrates in the known processes is still limited.
The aurone-derived aza diene has high reactivity due to strong driving force for recovering aromaticity. Over the last few years, organic reaction systems have been reported for such substrates: amine catalysis, carbene catalysis, phosphine catalysis, bronsted base catalysis. The recent immortal research group at the institute of chemical and physical university of Chinese academy of sciences has reported that the aurantione-derived azadiene can perform addition and cyclization reactions of some nucleophiles under the catalysis of Bronsted base. However, there have been no reports of the related reactions for catalyzing azadienes with bronsted acids.
Disclosure of Invention
Therefore, the Bronsted acid catalytic system provides a new strategy for other asymmetric reactions of the azadiene.
The invention aims to provide a method for synthesizing chiral hetero-triarylmethane by asymmetric indole addition reaction, which has the advantages of simple and practical operation, easily obtained raw materials, high enantioselectivity, good yield, identical reaction conditions, good tolerance of functional groups of substrates and the like.
In order to achieve the purpose, chiral bronsted acid is used as a catalyst, azadiene is used as a substrate, and asymmetric indole addition reaction is carried out to synthesize chiral hetero triarylmethane.
The technical scheme of the invention is as follows:
in one aspect, a method for synthesizing chiral hetero-triarylmethane is provided, the method uses chiral Bronsted acid as a catalyst, uses aza-diene as a substrate, and synthesizes chiral hetero-triarylmethane by asymmetric indole addition reaction, and the reaction formula of the method is as follows:
Figure BDA0001986936030000021
in the formula:
R1is H or C1-7The alkyl, the phenyl or the benzene ring containing substituent, wherein the substituent is halogen or C1-C20At least one of the alkyl substituents of (a);
R2is H or C1-7The alkyl, the phenyl or the benzene ring containing substituent, wherein the substituent is halogen or C1-C20At least one of the alkyl substituents of (a);
R3is H or C1-7The alkyl, the phenyl or the benzene ring containing substituent, wherein the substituent is halogen or C1-C20At least one of the alkyl substituents of (a);
ar 'and Ar' are one independently selected from phenyl or benzene ring containing substituent, and the substituent is halogen, naphthyl or C1-C20At least one alkyl substituent of (a).
Based on the technical scheme, preferably, the chiral bronsted acid is chiral phosphoric acid.
Based on the technical scheme, preferably, the organic solvent is one or a mixture of two of tetrahydrofuran, dichloromethane, trichloromethane, toluene, p-xylene and mesitylene.
Based on the technical scheme, the reaction temperature of the method is preferably-20-30 ℃.
Based on the technical scheme, preferably, the method comprises the following specific reaction steps:
adding azadiene, Bronsted acid and an organic solvent into a reaction bottle, putting into a cold bath at the temperature of-20 ℃, then adding indole, stirring for reaction for 48-72h, and directly carrying out column chromatography (the volume ratio of eluent petroleum ether to ethyl acetate is 5:1) to obtain a corresponding chiral hetero-triarylmethane compound; the molar ratio of the aza diene to the asymmetrically added indole to the catalyst is 1:1.0-5.0: 0.05-1.00. The yield was isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography.
Based on the technical scheme, preferably, the reaction is an addition reaction of asymmetric indole on the azadiene to synthesize chiral hetero-triarylmethane, and the molar ratio of the azadiene to the indole to the catalyst is 1:1.0: 0.05; r1Is hydrogen, R2Is hydrogen, R3Hydrogen, R is Ts, Ar 'is naphthyl, Ar' is 7 methylindole, the Bronsted acid is (R) -TRIP, the unsymmetrically added indole is simple unsubstituted indole, the organic solvent is mesitylene, the temperature is-20 ℃, and the enantiomeric excess is 99%.
Based on the technical scheme, preferably, the chiral phosphoric acid is one of binaphthyl skeleton and hydrogen octabinaphthyl skeleton chiral phosphoric acid with different 2, 2' positions, the substituted substituent is aryl or silicon base, and the axial chirality of the chiral phosphoric acid can be one of R or S.
Based on the technical scheme, it is further preferable that the chiral phosphoric acid is (R) -TRIP.
Advantageous effects
The invention has the following advantages
1. The raw materials are simple and easy to obtain, and the operation is simple.
2. High reaction activity, complete conversion of raw materials, simple post-treatment and capability of obtaining a high-purity product.
3. Good stereoselectivity, and can obtain single diastereoisomer with high enantioselectivity.
4. The tolerance to functional groups is good, and the reaction conditions are mild.
Detailed Description
The present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples.
Examples 1 to 13
And (3) optimizing conditions: the kind of the organic solvent, the kind of the catalyst and the temperature are changed.
Adding azadiene, chiral phosphoric acid and an organic solvent into a reaction bottle, putting into a cold bath at the temperature of-20 ℃, then adding indole, stirring for reaction for 48-72h, and directly carrying out column chromatography (the volume ratio of eluent petroleum ether to ethyl acetate is 5:1) to obtain a corresponding chiral hetero-triarylmethane compound; the molar ratio of the aza-diene to the asymmetrically added indole to the catalyst is 1:1.0: 0.05. The yield is the separation yield, the types of the organic solvent, the types of the catalyst and the reaction temperature are changed, the enantiomeric excess of the product is measured by a chiral liquid chromatography, and the specific results are shown in the table.
Figure BDA0001986936030000031
TABLE 1 optimization of conditions for the synthesis of chiral hetero-triarylmethanes
Figure BDA0001986936030000032
Figure BDA0001986936030000041
Examples 14 to 38
Asymmetric addition reaction to synthesize a series of chiral hetero-triarylmethane compounds.
Adding azadiene, chiral phosphoric acid A1 and mesitylene into a reaction bottle, putting into a cold bath at the temperature of-20 ℃, adding indole, stirring for reaction for 48-72 hours, and performing direct column chromatography (the volume ratio of eluent petroleum ether to ethyl acetate is 5:1) to obtain a corresponding chiral hetero triarylmethane compound; the molar ratio of the aza-diene to the asymmetrically added indole to the catalyst is 1:1.0: 0.05. The yield was isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography. The variety of starting materials and substrates in the reaction was varied to give 25 different examples, and the varied varieties are shown in Table 2.
Figure BDA0001986936030000042
TABLE 2 asymmetric addition Synthesis of a series of chiral hetero-triarylmethanes
Figure BDA0001986936030000043
Figure BDA0001986936030000051
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3aa):95mg,96％yield,yellow solid,m.p.＝106-108℃,newcompound,Rf＝0.25(hexanes/ethyl acetate 5:1),
Figure BDA0001986936030000052
121.0,119.8,118.8,118.5,114.0,113.1,111.5,111.3,38.5,20.9.HPLC:Chiralcel IC column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 21.2min(major)and 23.9min.HRMS Calculated For C30H28N3O3S[M+NH4]+510.1846,found:510.1849.
(+)-N-(2-((2-Methyl-1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamid e(3ab):91mg,90％yield,pale yellow solid,m.p.＝111-113℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝5:1),79％ee,[α]20 D＝+74.66(c0.90,EtOAc).1H NMR(400MHz,CDCl3)
Figure BDA0001986936030000053
HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 10.6min(major)and 13.0min.HRMS Calculated ForC31H26N2NaO3S[M+Na]+529.1556,found:529.1555.
(+)-Methyl-3-((3-((4-methylphenyl)sulfonamido)benzofuran-2-yl)(phenyl)methyl)-1H-indole-4-carboxylate(3ac):94mg,85％yield,white solid,m.p.＝113-114℃,new compound,Rf＝0.10(hexanes/ethyl acetate＝5:1),89％ee,[α]20 D＝+119.14(c 0.94,EtOAc).1H NMR(400MHz,DMSO-d6)
Figure BDA0001986936030000061
126.8,126.3,126.0,124.1,124.0,122.8,122.7,121.3,120.0,119.8,115.7,113.8,112.8,111.3,51.6,38.9,20.7.HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 8.1min and 24.6min(major).HRMS Calculated For C32H26KN2O5S[M+K]+589.1194,found:589.1192.
(+)-N-(2-((5-Chloro-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide
Figure BDA0001986936030000062
134.7,129.3,128.2,128.1,127.2,126.7,126.6,125.8,125.6,124.3,123.1,122.8,121.0,119.9,117.9,113.9,113.3,113.2,111.3,38.3,20.8.HPLC:Chiralcel AD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time9.9min(major)and 12.1min.HRMS Calculated For C30H27ClN3O3S[M+NH4]+544.1456,found:544.1457.
(+)-N-(2-((5-Methoxy-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ae):96mg,92％yield,white solid,m.p.＝105-106℃,newcompound,Rf＝0.20(hexanes/ethyl acetate＝5:1),92％ee,[α]20 D＝+89.51(c 1.04,EtOAc).1H NMR(400MHz,CDCl3)8.00(s,1H),7.59
Figure BDA0001986936030000063
254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time13.4min(major)and 20.2min.HRMS Calculated For C31H25N2O4S[M-H]-521.1540,found:521.1565.
(+)-N-(2-((5-(Benzyloxy)-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3af)105mg,88％yield,pale yellow solid,m.p.＝100-101℃,new compound,Rf＝0.45(hexanes/ethyl acetate＝5:1),88％ee,[α]20 D＝+77.74(c 0.40,EtOAc).1H NMR(400MHz,CDCl3)7.98(d,J＝1.8Hz,1H),7.58(d,J＝8.3Hz,2H),7.41-7.29(m,6H),7.25-7.16(m,7H),7.13-7.08(m,
Figure BDA0001986936030000064
0.8mL/min,retention time 18.1min(major)and 22.2min.HRMS CalculatedFor C37H34N3O4S[M+NH4]+616.2265,found:616.2269.
(+)-4-Methyl-N-(2-((6-methyl-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamid
Figure BDA0001986936030000071
132.4,129.7,128.6,128.5,127.7,126.9,126.2,124.4,123.2,122.9,121.7,119.7,119.2,115.2,113.2,111.7,111.3,39.9,21.8,21.6.HPLC:Chiralcel AD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time19.3min and 21.2min(major).HRMS Calculated For C31H26KN2O3S[M+K]+542.1296,found:542.1293.
(+)-4-Methyl-N-(2-((7-methyl-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamid
Figure BDA0001986936030000072
CDCl3)155.7,153.3,144.0,140.2,136.3,135.9,129.6,128.6,128.4,127.6,126.9,126.2,126.1,124.4,123.3,123.2,122.9,120.5,120.0,119.7,117.3,115.7,113.0,111.6,39.9,21.5,16.6.HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 12.8min and 15.6min(major).HRMSCalculated For C31H25N2O3S[M-H]-505.1591,found:505.1604.
(-)-N-(2-((1H-Indol-3-yl)(o-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ba)94mg,93％yield,white solid,m.p.＝95-97℃,newcompound,Rf＝0.25(hexanes/ethyl acetate＝5:1),93％ee,[α]20 D＝-54.68(c 0.94,EtOAc).1H NMR(400MHz,CDCl3)8.01(s,1H),7.48(d,J＝8.2Hz,
Figure BDA0001986936030000073
Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time12.2min and 16.6min(major).HRMS Calculated For C31H26KN2O3S[M+K]+545.1296,found:545.1291.
(+)-N-(2-((1H-Indol-3-yl)(m-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ca)89mg,88％yield,white solid,m.p.＝236-238℃,newcompound,Rf＝0.30(hexanes/ethyl acetate＝5:1),
Figure BDA0001986936030000074
column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retentiontime 11.7min and 22.3min(major).HRMS Calculated For C31H26KN2O3S[M+K]+545.1296,found:545.1300.
(+)-N-(2-((1H-Indol-3-yl)(p-tolyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3da)91mg,90％yield,pale yellow solid,m.p.＝103-104℃,new compound,Rf＝0.30(hexane s/ethyl acetate＝
Figure BDA0001986936030000081
AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 11.9min and 23.4min(major).HRMS Calculated For C31H26KN2O3S[M+K]+545.1296,found:545.1292.
(+)-N-(2-((1H-Indol-3-yl)(4-isopropylphenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamidee(3ea)95mg,89％yield,white solid,m.p.＝110-112℃,new compound,Rf＝0.45(hexanes/ethyl
Figure BDA0001986936030000082
123.5,122.7,121.0,119.7,118.8,118.5,114.2,112.9,111.5,111.3,38.1,33.0,23.9,23.8,20.9.HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 11.9min and 20.3min(major).HRMSCalculated For C33H30KN2O3S[M+K]+573.1609,found:573.1610.
(-)-N-(2-((1H-Indol-3-yl)(naphthalen-1-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3fa):97mg,89％yield,pale yellow solid,m.p.＝240-241℃,new compound,Rf＝0.30(hexanes/ethyl
Figure BDA0001986936030000083
133.5,131.0,129.1,128.7,127.2,126.5,126.3,126.1,126.0,125.5,125.4,124.5,124.2,123.8,122.8,121.2,119.8,118.7,118.6,114.5,113.5,111.6,111.3,35.2,20.9.HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 14.5min and 22.9min(major).HRMS Calculated ForC34H26KN2O3S[M+K]+581.1296,found:581.1301.
(+)-N-(2-((1H-Indol-3-yl)(4-methoxyphenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamidee(3ga)99mg,95％yield,tan solid,m.p.＝94-96℃,newcompound,Rf＝0.20(hexanes/ethyl acetate＝5:1),76％ee,[α]20 D＝+125.16(c 0.60,EtOAc).1H NMR(400MHz,CDCl3)7.99(s,1H),7.57(d,J＝
Figure BDA0001986936030000084
time 13.5min(major)and 16.6min.HRMS Calculated For C31H26KN2O4S[M+K]+561.1245,found:561.1250.
(+)-N-(2-((3-Bromophenyl)(1H-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ha)105mg,92％yield,white solid,m.p.＝116-118℃,newcompound,Rf＝0.20(hexanes/ethyl
Figure BDA0001986936030000091
HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 12.0min and 18.4min(major).HRMS Calculated ForC30H22BrN2O3S[M-H]-569.0540,found:569.0541.
(+)-N-(2-((3-Chlorophenyl)(1H-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ia):95mg,90％yield,pale yellow solid,m.p.＝234-236℃,new compound,Rf＝0.35(hexanes/ethyl acetate＝4:1),92％ee,[α]20 D＝+139.12(c0.80,EtOAc).1H NMR(400MHz,DMSO-d6)10.98(d,J
Figure BDA0001986936030000092
38.2,20.9.HPLC:Chiralcel AD-H column,254nm,30℃,n-Hexane/i-PrOH＝60/40,flow＝0.8mL/min,retention time 11.7min and 17.0min(major).HRMS CalculatedFor C30H23ClKN2O3S[M+K]+565.0749,found:565.0746.
(+)-N-(2-((4-Chlorophenyl)(1H-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3ja)95mg,90％yield,white solid,m.p.＝230-232℃,newcompound,Rf＝0.25(hexanes/ethyl acetate＝5:1),95％ee,[α]20 D＝+94.62(c 0.95,EtOAc).1H NMR(400MHz,CDCl3)8.07(s,1H),7.59(d,J＝
Figure BDA0001986936030000093
min(major).HRMS Calculated For C30H23ClKN2O3S[M+K]+565.0749,found:565.0745.
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)-5-methylbenzofuran-3-yl)-4-methylbenzenesulfonamide(3ka):90mg,89％yield,yellow solid,m.p.＝233-234℃,newcompound,Rf＝0.35(hexanes/ethyl acetate＝5:1),84％ee,[α]20 D＝+86.44(c 0.45,EtOAc).1H NMR(400MHz,DMSO-d6)10.91(s,1H),
Figure BDA0001986936030000094
111.6,110.9,38.6,20.9,20.8.HPLC:Chiralcel IC column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 19.3 min(major)and24.1min.HRMS Calculated For C31H25N2O3S[M-H]-505.1591,found:505.1608.
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)-6-methylbenzofuran-3-yl)-4-methylbenzenesulfonamide(3la):93mg,90％yield,yellow solid,m.p.＝214-216℃,newcompound,Rf＝0.35(hexanes/ethyl acetate＝5:1),91％ee,[α]20 D＝+70.85(c 0.47,EtOAc).1H NMR(400MHz,CDCl3)8.02(s,1H),7.60
Figure BDA0001986936030000101
＝90/10,flow＝0.7mL/min,retention time 22.1min(major)and 26.7min.HRMSCalculated For C31H25N2O3S[M-H]-505.1591,found:505.1627.
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-nitrobenzenesulfonamide(3ma):92mg,88％yield,pink solid,m.p.＝127-128℃,newcompound,Rf＝0.40(hexanes/ethyl acetate＝5:1),75％ee,[α]20 D＝+61.73(c 0.46,EtOAc).1H NMR(400MHz,CDCl3)8.01(s,1H),7.83-7.69(m,4H),
Figure BDA0001986936030000102
n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 18.5min and22.9min(major).HRMS Calculated For C29H25N4O5S[M+NH4]+541.1540,found:541.1543.
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)methanesulfonamide(3na):72 mg,86％yield,pink solid,m.p.＝110-112℃,newcompound,Rf＝0.20(hexanes/ethyl acetate＝5:1),85％ee,
Figure BDA0001986936030000103
115.3,113.1,112.0,111.5,40.2,40.1.HPLC:Chiralcel IC column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 24.9min(major)and28.3min.HRMS Calculated For C24H20N2NaO3S[M+Na]+439.1087,found:439.1085.
(+)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)methanesulfonamide(3oa):83mg,80％yield,yellow solid,m.p.＝175-177℃,newcompound,Rf＝0.45(hexanes/ethyl acetate＝5:1),83％ee,[α]20 D＝+84.74(c 0.40,EtOAc).1H NMR(400MHz,DMSO-d6)10.92(d,J＝1.6Hz,1H),9.93(s,
Figure BDA0001986936030000104
118.5,113.9,112.6,111.5,111.4,38.7,22.7,20.3.HPLC:Chiralcel AD-Hcolumn,254nm,30℃,n-Hexane/i-PrOH＝70/30,flow＝0.8mL/min,retention time12.2min and 18.1min(major).HRMS Calculated For C32H32N3O3S[M+NH4]+538.2159,found:538.2156.
(S)-(-)-N-(2-((1H-Indol-3-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide(3fh):104mg,93％yield,pink solid,m.p.＝145-146℃,newcompound,Rf＝0.50(hexanes/ethyl acetate＝5:1),99％ee,[α]20 D＝-92.99(c 0.40,EtOAc).1H NMR(400MHz,CDCl3)7.93(s,1H),7.86(d,J＝
Figure BDA0001986936030000111
127.9,127.6,126.4,126.4,126.4,126.0,125.7,125.6,124.5,124.1,123.7,123.3,123.2,120.6,120.3,120.1,116.8,115.6,114.0,111.6,36.8,21.6,16.7.HPLC:Chiralcel IC column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 18.0min(major)and 21.1min.HRMS Calculated For C35H32N3O3S[M+NH4]+574.2159,found:574.2161.
(+)-N-(2-((4-Chlorophenyl)(7-methyl-1H-indol-3-yl)methyl)benzofuran-3-yl)-4-methylbenzenesul fonamide(3jh):100mg,92％yield,pink solid,m.p.＝124-126℃,new compound,Rf＝0.45(hexanes/ethyl acetate＝5:1),98％ee,[α]20 D＝+102.66(c 0.30,EtOAc).1H NMR(400MHz,CDCl3)
Figure BDA0001986936030000112
mL/min,retention time 29.1min and 31.4min(major).HRMS Calculated ForC31H29ClN3O3S[M+NH4]+558.1613,found:558.1614.
(+)-4-Methyl-N-(2-((1-methyl-1H-indol-3-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide(3ai):50mg,49％yield,white solid,m.p.＝229-231℃,newcompound,Rf＝0.20(hexanes/ethyl
Figure BDA0001986936030000113
128.1,127.9,126.7,126.5,126.5,125.9,124.2,122.8,121.1,119.9,119.0,118.6,113.3,113.1,111.3,109.6,38.4,32.2,20.8.HPLC:Chiralcel IC column,254nm,30℃,n-Hexane/i-PrOH＝90/10,flow＝0.7mL/min,retention time 25.1min and28.0min(major).HRMS Calculated For C31H26N2NaO3S[M+Na]+529.1556,found:529.1554.
4-Methyl-N-(2-(phenyl(1H-pyrrol-3-yl)methyl)benzofuran-3-yl)benzenesulfonamide(5):70mg,65％yield,pink solid,m.p.＝256-257℃,new compound,Rf＝0.30(hexanes/ethyl acetate＝10:1),1％ee.1H NMR(400MHz,CDCl3)8.62(s,1H),7.62(d,J＝8.3Hz,2H),7.34(d,J＝8.3Hz,1H),
Figure BDA0001986936030000114
n-Hexane/i-PrOH＝70/30,flow＝0.7mL/min,retention time 6.9min(major)and 7.6min.HRMS Calculated For C26H23N2O3S[M+H]+443.1424,found:443.1421.

Claims (8)

1. A method for synthesizing chiral hetero-triarylmethane is characterized in that chiral Bronsted acid is used as a catalyst, azene derived aza diene is used as a substrate, indole is used as a nucleophilic reagent, and the chiral hetero-triarylmethane is synthesized by asymmetric addition reaction, wherein the reaction formula of the method is as follows:
Figure FDA0001986936020000011
in the formula:
R1is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
R2is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
R3is H, phenyl, C1-7An alkyl group or a benzene ring having a substituent; the substituent is halogen and C1-C20At least one of the alkyl substituents of (a);
r is sulfonyl;
ar 'and Ar' are phenyl or benzene ring containing substituent, and the substituent is halogen, naphthyl or C1-C20At least one alkyl substituent of (a).
2. The method according to claim 1, characterized in that said chiral bronsted acid is a chiral phosphoric acid.
3. The method according to claim 1, wherein the organic solvent is one or a mixture of two of tetrahydrofuran, dichloromethane, chloroform, toluene, p-xylene and mesitylene.
4. The process according to claim 1, wherein the reaction temperature of the process is-20 to 30 ℃.
5. The method according to claim 1, wherein the method comprises the following specific reaction steps:
adding azadiene and chiral Bronsted acid into a reaction bottle, then adding an organic solvent, adding indole after half an hour, stirring for reaction for 48-72 hours, and directly carrying out column chromatography to obtain the chiral hetero-triarylmethane; the molar ratio of the aza diene to the indole to the catalyst is 1:1.0-1.5: 0.05-1.00.
6. The method of claim 1, wherein: the reaction is to synthesize chiral hetero-triarylmethane by the asymmetric addition reaction of the azadiene and the indole, and the molar ratio of the azadiene to the indole to the catalyst is 1:1.0: 0.05; r1Is hydrogen, R2Is hydrogen, R3Hydrogen, R is Ts, Ar 'is naphthyl, Ar' is 7 methylindole, the Bronsted acid is (R) -TRIP, the organic solvent is mesitylene, the temperature is-20 ℃, and the enantiomeric excess is 99%.
7. The method of claim 2, wherein: the chiral phosphoric acid is one of binaphthyl skeleton and hydrogen octabinaphthyl skeleton chiral phosphoric acid with different 2, 2' positions, the substituted substituent is aryl or silicon base, and the axial chirality of the chiral phosphoric acid can be one of R or S.
8. The method of claim 7, wherein the chiral phosphoric acid is (R) -TRIP.
CN201910167900.8A 2019-03-06 2019-03-06 Method for synthesizing chiral hetero-triarylmethane Pending CN111662274A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910167900.8A CN111662274A (en) 2019-03-06 2019-03-06 Method for synthesizing chiral hetero-triarylmethane

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910167900.8A CN111662274A (en) 2019-03-06 2019-03-06 Method for synthesizing chiral hetero-triarylmethane

Publications (1)

Publication Number Publication Date
CN111662274A true CN111662274A (en) 2020-09-15

Family

ID=72381324

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910167900.8A Pending CN111662274A (en) 2019-03-06 2019-03-06 Method for synthesizing chiral hetero-triarylmethane

Country Status (1)

Country Link
CN (1) CN111662274A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634490A (en) * 2020-12-15 2022-06-17 中国科学院大连化学物理研究所 Method for synthesizing heterotriarylmethane by functionalizing 2, 3-disubstituted indole C6

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001159A (en) * 2014-04-23 2015-10-28 中国科学院大连化学物理研究所 Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001159A (en) * 2014-04-23 2015-10-28 中国科学院大连化学物理研究所 Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SADHANENDU SAMANTA等: "Ruthenium-catalyzed tandem annulation/arylation for the synthesis of unsymmetrical bis(heteroaryl)methanes", 《ORG. BIOMOL. CHEM.》 *
伍平 等: "3-吲哚醇和色醇的催化不对称脱水芳基化反应--双吲哚取代的三芳基甲烷类化合物的不对称合成", 《有机化学》 *
李中贤 等: "三芳基甲烷类化合物合成方法的研究进展", 《有机化学》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634490A (en) * 2020-12-15 2022-06-17 中国科学院大连化学物理研究所 Method for synthesizing heterotriarylmethane by functionalizing 2, 3-disubstituted indole C6

Similar Documents

Publication Publication Date Title
CN107501160B (en) Method for synthesizing axial chiral aryl indole through organic catalysis
CN112321481B (en) Chiral indole compound and preparation method thereof
Zhu et al. Recent advances for the synthesis of chiral sulfones with the sulfone moiety directly connected to the chiral center
CN107501163B (en) Method for synthesizing axial chiral aniline indole under catalysis of chiral phosphoric acid
Xie et al. Chiral Brønsted acid-catalyzed conjugate addition of indoles to azadienes: Enantioselective synthesis of hetero-triarylmethanes
CN105175328A (en) Method for synthesizing quinoline derivative by utilizing arylamine, aromatic aldehyde and ketone
CN106565742A (en) Indolone screw tetralin sulfo-pyran derivative and preparing method and application thereof
CN111662274A (en) Method for synthesizing chiral hetero-triarylmethane
Schmidt et al. Catalyst control over threefold stereogenicity: selective synthesis of atropisomeric sulfones with stereogenic C− S axes
Martí et al. H‐Bonded Counterion‐Directed Catalysis: Enantioselective Gold (I)‐Catalyzed Addition to 2‐Alkynyl Enones as a Case Study
CN111848623B (en) Method for synthesizing fluorine-containing chiral ketal amine by catalysis of chiral phosphoric acid
Bandini et al. New chiral diamino-bis (tert-thiophene): an effective ligand for Pd-and Zn-catalyzed asymmetric transformations
CN105712922A (en) Synthetic method of dihydropyrrole and pyrrole compounds
Massacret et al. Palladium (0)‐Catalyzed Asymmetric Synthesis of 1, 2, 3, 4‐Tetrahydro‐2‐vinylquinoxalines
CN114057785B (en) Synthesis method of chiral alpha-difluoromethylsilane compound
CN112812070B (en) Method for preparing benzodiazepine compound by high-efficiency catalysis of palladium pyridine
CN110627723B (en) Trifluoromethyl pyrazole derivative and application thereof
CN111825509B (en) Catalytic asymmetric synthesis method of chiral 3,4, 4-trisubstituted pyrrolidone compound
CN113444057A (en) Single-chiral-arm aminophenol sulfonamide ligand and application thereof in asymmetric catalysis
CN112174920A (en) Preparation method for synthesizing dihydropyrone compound containing 1, 3-eneyne functional group by using N-heterocyclic carbene as catalyst
CN113387937B (en) Method for synthesizing chiral pyrazole-containing triarylmethane compound
CN111100085A (en) Preparation method of 3-aryl-2H-benzo [ β ] [1,4] benzoxazine-2-one compound
JP2003510180A (en) Catalysts for asymmetric transfer hydrogenation
CN114605273B (en) Method for synthesizing arylaminophenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction
CN114437008B (en) Synthesis method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compound

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
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20200915