CN114437008B - Synthesis method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compound - Google Patents

Synthesis method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compound Download PDF

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CN114437008B
CN114437008B CN202210025616.9A CN202210025616A CN114437008B CN 114437008 B CN114437008 B CN 114437008B CN 202210025616 A CN202210025616 A CN 202210025616A CN 114437008 B CN114437008 B CN 114437008B
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黄海
谢红玲
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Changzhou University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, in particular to a method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds. 3-aryl oxetane compounds and phenolic compounds are used as raw materials, chiral phosphoric acid and metal Lewis acid are used as synergistic catalysts, and the products are synthesized under the room temperature condition for 24-72 hours. The reaction is simply post-treated to obtain a series of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds with high yield. Phenol compounds with various substituents and oxetanes with various substituents can be used as reaction substrates to obtain corresponding (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds.

Description

Synthesis method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compound
Technical Field
The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, in particular to a method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds. Wherein 3-aryl oxetane and phenol are used as raw materials, chiral phosphoric acid and metal Lewis acid are used as synergistic catalysts, and the method for synthesizing the (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds is simple and efficient at room temperature.
Background
2, 3-dihydrobenzofurans, also known as coumarins, are common structural motifs that are widely found in natural compounds as key molecular backbones, including furanoquinoline a, retinoids and isopsoralen a. They are also found in drugs with a wide range of biological activities, such as CB2 receptor agonists HCV NS5B inhibitors and DNA-PK inhibitors, etc.
Most importantly, all of the structures described above have all carbon quaternary stereogenic centers at the 3-position of coumarin. Thus, it is necessary and highly desirable to construct enantiomerically enriched 2, 3-dihydrobenzofurans with all-carbon quaternary stereocenters, and is also a challenging task in heterocompound synthesis. Chiral ligand enhanced metal catalyzed enantioselective hydroarylation of allylic aryl ethers is a major strategy for this coumarin moiety, developed by Brown, zhang and Kong. Furthermore, there is currently a lack of effective methods for such frameworks. (see: brown, M.K., J.Am.Chem.Soc.2015,137,14578-14581; zhang, J., angew.chem. Int. Ed.2018,57,10373-10377; kong, W., J. Am. Chem. Soc.2018,140, 12364-12368.).
Through recent efforts by chemists, chiral Phosphoric Acid (CPA) -catalyzed asymmetric ring opening reactions of oxetanes have become the most powerful tool for enantiomerically-enriched compounds. However, the catalytic mode of oxetane is not yet rich enough for the diversified needs of organic development, and innovation is needed.
Disclosure of Invention
In view of the shortcomings in the background art, as a continuous work and new method for synthesizing chiral coumarin, the invention researches the enantioselective [3+2] cycloaddition reaction of oxetane catalyzed by first metal and phosphoric acid, and effectively synthesizes 2, 3-dihydrobenzofuran with all-carbon quaternary stereogenic center under mild conditions, which is a new catalytic mode in the field of oxetane. And this work has successfully developed a new example of combining a metal lewis acid with chiral phosphoric acid as a co-catalyst.
The invention provides a synthetic method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds. Wherein 3-aryl oxetane compounds and phenolic compounds are used as raw materials, CPA V is used as a catalyst, and In (OTf) 3 Is a Lewis acid, and is a simple and efficient method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds at room temperature. The specific process of the reaction is as follows:
the structure of CPA V is:
of these, the above Ar substituents are preferred, with CPA V catalysts of this formula being most effective, and if the substituents are altered, they result in poor enantioselectivity.
The structural formula of the 3-aryl oxetane compound is as follows:
wherein Ar is 1 The radicals are aryl, heteroaryl, substituted aryl and substituted heteroaryl; ar on phenol 2 The radical is any one of aryl and substituted aryl. The aryl is selected from one of phenyl, naphthyl, phenanthryl, anthryl, acenaphthylenyl, fluorenyl, pyrenyl and fluoranthenyl; heteroaryl is selected from one of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl and purinyl; the substituents in the substituted aryl and substituted heteroaryl groups are each independently selected from one of fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, alkenyl, alkynyl, nitro, mercapto, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, alkyl ester groups, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy, haloalkyloxy, and cycloalkylalkyl.
The reaction conditions are as follows: the synthesis reaction is carried out for 24-72 hours at room temperature.
The catalyst is chiral phosphoric acid catalyst, and the dosage is 10-15mol% of the mole number of the 3-aryl oxetane compound raw material;
the molar ratio of 3-aryl oxetane compound to phenolic compound is 1:1 to 1:3, a step of;
the metal Lewis acid used was In (OTf) 3 ，Yb(OTf) 3 ，Sc(OTf) 3 AgOTf or Cu (OTf) 2 The molar ratio of the amount thereof to the 3-aryloxetane Ding Huanma was 10mol%.
Preferably, the invention is carried out In the presence of CPA V as catalyst, in (OTf) 3 The reaction effect is optimal under the condition of Lewis acid. And the experimental result shows that if the chiral phosphoric acid catalyst is not added, the product obtained by the reaction has no chirality and low yield. If Lewis acid is not added, the reaction will not occur. CPA V is therefore a catalyst and In (OTf) 3 There is a synergy between the lewis acids.
The reaction post-treatment is simple and convenient, and the pure compound can be obtained only by a simple column chromatography separation method by using a mixed solvent of petroleum ether and ethyl acetate as an eluent.
Compared with the prior art, the invention has the beneficial effects that: a catalytic enantioselective [3+2] cycloaddition reaction for the synthesis of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofurans has been developed. The method provides a way to synthesize various 2, 3-dihydrobenzofuran backbones with high enantioselectivity from the simple starting material 3-aryloxetane. In this reaction, the combination of lewis acid and CPAs as a dual catalyst has excellent properties in terms of improving yield and enantioselectivity, which is a new catalytic mode in oxetane chemistry. Future directions will focus on expanding phenol to aniline to develop chiral indolines.
Detailed Description
The 3-aryloxetane starting materials in the examples can be synthesized by a commercially available or known literature (see: 1.Org. Lett.2020,22,8219-8223;2.Chem. Eur. J.2016,22, 16271-16276.) the naphthol starting materials in the examples can be synthesized by a commercially available or known literature (see: 1.J. Am. Chem. Soc.2020,142,9872-9878;2.Angew. Chem., int. Ed.2018,57,4622-4626;3.J. Am. Chem. Soc.2016,138, 16553-16560.)
The present invention will be described in detail with reference to the following examples, which are presented in the following examples:
example 1 (R) -4- (1- (hydroxymethyl) -1,2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(1-(Hydroxymethyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 2-naphthol (0.3 mmol) In DCM (6.0 mL) at room temperature was added catalyst CPA-V (0.03 mmol,10 mol%) followed by In (OTf) 3 (0.03 mmol,10 mol%). The reaction is carried outThe mixture was stirred at room temperature for 60 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 78% yield (68.3 mg), 98% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.30(s,1H),7.84-7.85(m,2H), 7.44-7.39(m,1H),7.28-7.13(m,5H),6.78(dd,J 1 ＝6.4Hz,J 2 ＝2.0Hz,2H),5.05(d, J＝8.8Hz,1H),4.50(d,J＝9.2Hz,1H),4.45(dd,J 1 ＝11.2Hz,J 2 ＝6.0Hz,1H), 4.33(dd,J 1 ＝10.8Hz,J 2 ＝4.4Hz,1H),4.20(dd,J 1 ＝6.0Hz,J 2 ＝5.2Hz,1H)ppm. 13 c NMR (100 MHz, acetate-d 6) delta 159.8,156.8,136.2,131.9,131.1,131.0,129.8, 129.4,127.0,123.9,123.2,123.1,116.1,113.0,83.8,66.2,57.7ppm mass spectrometry data: HRMS (CI+) calculated for C19H16NaO3[ M+Na]+:315.0992,Found:315.0994.
Comparative example 1
In (OTf) was not added In the reaction compared with example 1 3 Lewis acid and other operations are the same as in example 1.
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 2-naphthol (0.3 mmol) in DCM (6.0 mL) at room temperature was added catalyst CPA-V (0.03 mmol,10 mol%) and the reaction mixture was stirred at room temperature for 60 hours. The reaction does not yield the target product.
Comparative example 2
In comparison with example 1, the reaction was carried out without adding CPA-V as a catalyst, and the other operations were the same as in example 1.
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 2-naphthol (0.3 mmol) In DCM (6.0 mL) at room temperature was added In (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and then the residue was filtered through a short column of silica gel, and the yield of the target compound was 51% by NMR analysis, but the reaction had no enantiomerSelectivity.
Comparative example 3
In comparison with example 1, CPA-V was exchanged for another chiral phosphoric acid catalyst and the other operations were the same as example 1.
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 2-naphthol (0.3 mmol) In DCM (6.0 mL) at room temperature was added catalyst CPA-IV (0.03 mmol,10 mol%) followed by In (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was diluted with ethyl acetate and concentrated, and the residue was purified directly by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3:1), yield 47%,44% ee.
Example 2 (R) -4- (1- (hydroxymethyl) -7-methyl-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(1-(Hydroxymethyl)-7-methyl-1,2-dihydronaphtho[2,1-b]furan-1-yl)phen ol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-methyl-2-naphthol (0.3 mmol) In DCM (6.0 mL) was added catalyst CPA-V (0.03 mmol,10 mol%) followed by In (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 71% yield (65.1 mg), 99% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(300MHz,acetone-d6)δ8.28(s,1H),7.72(dd,J 1 ＝8.7Hz, J 2 ＝3.9Hz,2H),7.28-7.21(m,3H),7.10-7.03(m,2H),6.77(td,J 1 ＝9.0Hz,J 2 ＝2.4 Hz,2H),5.05(d,J＝9.0Hz,1H),4.51-4.43(m,2H),4.33(dd,J 1 ＝11.1Hz,J 2 ＝4.8 Hz,1H),4.18(dd,J 1 ＝6.0Hz,J 2 ＝5.1Hz,1H),2.25(s,3H)ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 160.0,156.8,136.5,136.4,132.2,130.8,129.8,129.4,129.3, 125.5,122.9,122.4,116.1,112.1,83.8,66.2,57.7,22.0ppm mass spectrometry data: HRMS (CI+) calculated for C20H18O3[ M]:306.1256,Found:306.1271.
Example 3: (R) -4- (1- (hydroxymethyl) -7-cyclohexyl-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(7-Cyclohexyl-1-(hydroxymethyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)p henol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-cyclohexyl-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.045 mmol,15 mol%) followed by Yb (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 77% yield (86.4 mg), 97% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(300MHz,acetone-d6)δ8.27(s,1H),7.73(d,J＝8.8Hz, 1H),7.63(s,1H),7.33(d,J＝8.8Hz,1H),7.26(d,J＝8.8Hz,2H),7.14(dd,J 1 ＝5.2 Hz,J 2 ＝1.6Hz,1H),7.11(d,J＝8.8Hz,1H),6.77(d,J＝8.8Hz,2H),5.03(d,J＝ 8.8Hz,1H),4.51-4.41(m,2H),4.31(dd,J 1 ＝11.2Hz,J 2 ＝5.2Hz,1H),4.18(t,J＝ 5.2Hz,1H),2.62-2.53(m,1H),1.90-1.80(m,4H),1.73(d,J＝12.8Hz,1H), 1.56-1.36(m,4H),1.35-1.26(m,1H)ppm. 13 C NMR(125.5MHz,acetone-d6)δ 159.3,156.9,142.8,136.4,131.3,130.8,130.5,129.5,127.2,126.5,123.9,123.1, 116.1,116.0,112.9,83.7,66.3,57.8,45.2,35.2,35.1,27.7,26.9ppm mass spectral data: HRMS (CI+) calculated for C25H26O3[ M]:374.1882,found:374.1872.
Example 4: (R) -4- (1- (hydroxymethyl) -7-Bromo-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol (R) -4- (7-Bromo-1- (hydroxyymethyl) -1, 2-dihydroaphtho [2,1-b ] furan-1-yl) phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-bromo-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added at room temperature the catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 60 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 61% yield (67.9 mg), 95% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.34(s,1H),8.04(d,J＝1.2Hz, 1H),7.79(d,J＝8.8Hz,1H),7.40-7.28(m,2H),7.22(t,J＝8.4Hz,3H),6.79(d,J＝8.8Hz,2H),5.02(d,J＝8.8Hz,1H),4.50(d,J＝8.8Hz,1H),4.43-4.32(m,2H), 4.30-4.25(m,1H)ppm. 13 c NMR (75.5 mhz, acetone-d 6) delta 160.3,157.0,135.7, 132.2,131.6,130.45,130.42,129.9,129.3,126.2,123.8,116.3,123.8,116.2,114.3, 84.0,66.3ppm mass spectrometry data: HRMS (CI+) calculated for C19H15BrO3[ M ]]+: 370.0205,found:370.0209.
Example 5: (R) -4- (1- (Hydroxymethyl) -7-phenyl-1,2-dihydronaphtho [2,1-b ] furan-1-yl) phenol (R) -4- (1- (hydromethyl) -7-phenyl-1, 2-dihydroaphtho [2,1-b ] furan-1-yl) phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-phenyl-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.03 mmol,10 mol%) followed by Sc (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 90% (99.5 mg), 97% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.36(s,1H),8.11(s,1H),7.88(d, J＝8.8Hz,1H),7.70(d,J＝7.6Hz,2H),7.53(t,J＝10.4Hz,2H),7.44(t,J＝7.6Hz, 2H),7.33(d,J＝7.2Hz,1H),7.30(d,J＝8.4Hz,2H),7.20(d,J＝8.8Hz,1H),6.82 (d,J＝8.4Hz,2H),5.08(d,J＝8.8Hz,1H),4.54(d,J＝8.8Hz,1H),4.45(dd,J 1 ＝10.8Hz,J 2 ＝6.0Hz,1H),4.45(dd,J 1 ＝10.8Hz,J 2 ＝4.4Hz,1H),4.29(t,J＝5.2Hz, 1H)ppm. 13 c NMR (75.5 MHz, acetone-d 6) delta 159.8,156.6,141.5,135.9,135.5, 131.4,131.1,130.8,129.5,129.2,127.6,127.4,127.3,126.1,124.4,122.9,115.9, 113.3,83.7,66.1,57.5ppm mass spectrometry data: HRMS (CI+) calculated for C25H20O3[ M]: 368.1412,found:368.1417.
Example 6: (R) -4- (1- (hydroxymethyl) -3, 5-bistrifluoro-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(7-(3,5-bis(trifluoromethyl)phenyl)-1-(hydroxymethyl)-1,2-dihydronaphth o[2,1-b]furan-1-yl)phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6- (3, 5-bistrifluoromethyl) -2-naphthol (0.3 mmol) in DCM (6.0 mL) at room temperature was added the catalyst CPA-V (0.03 mmol,10 mol%),sc (OTf) is then added 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 80% (120.1 mg), 96% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.38(d,J＝1.2Hz,1H),8.36(s, 2H),8.33(s,1H),8.00(s,1H),7.97(d,J＝8.8Hz,1H),7.70(dd,J 1 ＝8.8Hz,J 2 ＝1.6 Hz,1H),7.57(d,J＝8.8Hz,1H),7.29(d,J＝8.8Hz,2H),7.25(d,J＝8.8Hz,1H), 6.81(d,J＝8.4Hz,2H),5.08(d,J＝9.2Hz,1H),4.55(d,J＝9.2Hz,1H),4.47(dd, J 1 ＝10.8Hz,J 2 ＝6.0Hz,1H),4.39(dd,J 1 ＝10.8Hz,J 2 ＝4.8Hz,1H),4.30(t,J＝ 4.8Hz,1H)ppm. 13 c NMR (125 mhz, acetone-d 6) δ 160.8,157.0,144.5,136.0, 132.7 (q, j=32.5 Hz), 132.4,132.1,131.9,131.2,129.5,128.1,125.9,125.2,124.4 (q, j=208.8 Hz), 123.1,121.2 (m), 116.2,116.1,114.0,84.1,66.3,57.7ppm mass spectrometry data: HRMS (CI+) calculated for C27H18F6O3[ M ]]:504.1160,Found:504.1169.
Example 7: (R) -4- (1- (hydroxymethyl) -7-phenylethynyl-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(1-(Hydroxymethyl)-7-(phenylethynyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)p henol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-phenylethynyl-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.045 mmol,15 mol%) followed by Sc (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. Reaction mixingThe residue was purified directly by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3:1) in 57% yield (69.3 mg), 99% ee, as a white solid.
Nuclear magnetic data: 1 H NMR(300MHz,acetone-d6)δ8.35(s,1H),8.06(d,J＝1.5Hz, 1H),7.84(d,J＝9.0Hz,1H),7.58-7.50(m,2H),7.48-7.30(m,5H),7.29-7.18(m, 3H),6.84-6.77(m,2H),5.06(d,J＝9.0Hz,1H),4.52(d,J＝9.0Hz,1H),4.48-4.34 (m,2H),4.33-4.24(m,1H)ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 160.7,156.8, 135.7,133.2,132.1,131.3,131.2,130.5,129.4,129.3,129.2,129.1,124.3,124.2, 123.6,117.6,116.1,113.9,90.6,89.4,84.0,66.2,57.5ppm mass spectrometry data: HRMS (CI+) calculated for C27H20O3[ M]:392.1412,Found:392.1419.
Example 8: (R) -1- (Hydroxymethyl) -1- (4-hydroxyphenyl) -1, 2-dihydronaphthalene [2,1-b ] furan-7-carbonitrile (R) -1- (hydroxylethyl) -1- (4-hydroxyphenyl) -1, 2-dihydroapahtho [2,1-b ] furan-7-carb onile
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-cyano-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added at room temperature the catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2.5:1) in 45% yield (42.6 mg), 94% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(300MHz,acetone-d6)δ8.37(s,1H),8.35(d,J＝1.5Hz, 1H),7.97(d,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.41(dd,J 1 ＝7.8Hz,J 2 ＝1.8 Hz,1H),7.32(d,J＝9.0Hz,1H),7.27-7.18(m,2H),6.83-6.75(m,2H),5.06(d,J＝ 9.0Hz,1H),4.56(d,J＝9.0Hz,1H),4.43-4.37(m,2H),4.36-4.31(m,1H)ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 162.4,157.0,135.8,135.3,133.4,132.2,129.7, 129.2,127.3,125.3,124.1,119.9,116.2,114.8,106.2,84.4,66.1,57.4ppm mass spectrometry data: HRMS (CI+) calculated for C20H16NO3[ M+H+]:318.1125,found:318.1131.
Example 9: (R) -4- (1- (hydroxymethyl) -7-methoxy-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(1-(Hydroxymethyl)-7-methoxy-1,2-dihydronaphtho[2,1-b]furan-1-yl)phe nol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 6-methoxy-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added at room temperature the catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 60 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2.5:1) in 70% yield (67.2 mg), 95% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.29(s,1H),7.69(d,J＝8.8Hz, 1H),7.33(d,J＝9.2Hz,1H),7.26(dd,J 1 ＝5.6Hz,J 2 ＝2.4Hz,3H),7.11(d,J＝8.8 Hz,1H),6.89(dd,J 1 ＝9.2Hz,J2＝2.0Hz,1H),6.77(d,J＝8.4Hz,2H),5.00(d,J＝ 8.8Hz,1H),4.49-4.38(m,2H),4.30(dd,J 1 ＝10.8Hz,J 2 ＝4.8Hz,1H),4.19(t,J＝ 5.2Hz,1H),3.83(s,3H)ppm. 13 c NMR (75.5 MHz, acetone-d 6) delta 158.2,156.8, 156.1,136.2,132.0,129.7,129.4,127.1,125.4,123.6,119.5,116.0,113.2,108.1, 83.5,66.4,57.8,55.5ppm mass spectrometry data: HRMS (CI+) calculated for C20H18O4[ M]: 322.1205,Found:322.1212.
Example 10: (R) -4- (1- (Hydroxymethyl) -8-methoxy-1,2-dihydronaphtho [2,1-b ] furan-1-yl) phenol (R) -4- (1- (hydroymethyl) -8-methoxy-1, 2-dihydroaphtho [2,1-b ] furan-1-yl) phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 7-methoxy-2-naphthol (0.3 mmol) In DCM (6.0 mL) was added catalyst CPA-V (0.03 mmol,10 mol%) followed by In (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2.5:1) in 46% yield (44.5 mg), 98% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.29(s,1H),7.69(t,J＝8.0Hz, 2H),7.33(d,J＝8.4Hz,2H),6.98(d,J＝8.8Hz,1H),6.87-6.70(m,4H),5.04(d,J＝ 8.8Hz,1H),4.52(d,J＝8.8Hz,1H),4.45(dd,J 1 ＝10.8Hz,J 2 ＝4.0Hz,1H), 4.34-4.27(m,1H),4.26-4.21(m,1H),3.55(s,3H)ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 160.1,158.7,156.7,135.8,133.0,131.1,130.7,129.6,126.2,122.6, 116.0,115.6,110.3,102.7,83.6,65.8,57.4,55.1ppm mass spectrometry data: HRMS (CI+) calculated for C20H18O4[ M]:322.1205,Found:322.1212.
Example 11: (R) -4- (1- (hydroxymethyl) -8-bromo-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(8-Bromo-1-(hydroxymethyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)pheno l
To 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 7-bromo-2 naphthol (0.3 mmol) in DCM (6.0 mL) at room temperatureTo the solution was added catalyst CPA-V (0.03 mmol,10 mol%) followed by Cu (OTf) 2 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 60 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 68% yield (75.7 mg), 98% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.35(s,1H),7.82(d,J＝8.8Hz, 1H),7.78(d,J＝8.8Hz,1H),7.61(s,1H),7.30(dd,J 1 ＝8.8Hz,J 2 ＝1.6Hz,1H), 7.25(d,J＝8.8Hz,2H),7.20(d,J＝8.8Hz,1H),6.81(d,J＝8.4Hz,2H),5.01(d,J ＝8.8Hz,1H),4.51(d,J＝8.8Hz,1H),4.38(d,J＝4.4Hz,2H),4.36-4.30(m,1H) ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 160.7,156.9,135.4,133.1,131.7,131.2, 129.3,129.2,126.3,126.1,122.7,120.9,116.2,113.6,84.0,66.1,57.5ppm mass spectrometry data: HRMS (CI+) calculated for C19H15BrO3[ M ]]+:370.0205,found:370.0202.
Example 12: (R) -4- (1- (hydroxymethyl) -8-phenyl-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(1-(Hydroxymethyl)-8-phenyl-1,2-dihydronaphtho[2,1-b]furan-1-yl)phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 7-phenyl-2-naphthol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.045 mmol,15 mol%) followed by Cu (OTf) at room temperature 2 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, and the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 66% yield (72.6 mg), 97% ee,the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.34(s,1H),7.90(d,J＝8.8Hz, 1H),7.82(d,J＝8.8Hz,1H),7.72(s,1H),7.53(d,J＝8.8Hz,1H),7.48(d,J＝7.2 Hz,2H),7.43-7.27(m,5H),7.18(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,1H),5.09(d, J＝8.8Hz,1H),4.57(d,J＝8.8Hz,1H),4.49(dd,J 1 ＝11.2Hz,J 2 ＝6.0Hz,1H), 4.43(dd,J 1 ＝10.8Hz,J 2 ＝4.4Hz,1H),4.34(t,J＝5.2Hz,1H)ppm. 13 c NMR (75.5 MHz, acetate-d 6) delta 159.9,156.7,141.7,139.0,135.8,131.9,130.6,130.2,129.9, 129.5,129.4,128.0,127.6,123.5,122.5,121.6,115.9,112.9,83.6,66.1,57.5ppm mass spectrometry data: HRMS (CI+) calculated for C25H20O3[ M]:368.1412,found:368.1414.
Example 13: (R) -4- (3- (hydroxymethyl) -4,5, 6-trimethoxy-1, 2-dihydronaphtho [2,1-b ] furan-1-yl) phenol
(R)-4-(3-(Hydroxymethyl)-4,5,6-trimethoxy-2,3-dihydrobenzofuran-3-yl)phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 3,4, 5-trimethoxy-phenol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.045 mmol,15 mol%) followed by Cu (OTf) at room temperature 2 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) in 60% yield (59.7 mg), 96% ee, the compound was a transparent oil.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ8.23(s,1H),7.15(d,J＝8.4Hz, 2H),6.76(d,J＝8.4Hz,2H),6.29(s,1H),4.80(d,J＝8.8Hz,1H),4.47(d,J＝8.4 Hz,1H),4.19(d,J＝10.4Hz,1H),4.13(d,J 1 ＝10.4Hz,1H),3.98(brs,1H),3.81(s, 3H),3.70(s,3H),3.62(s,3H)ppm. 13 c NMR (75.5 MHz, acetone-d 6) delta 157.6,156.6, 155.6,151.1,136.7,136.5,128.7 (2C), 115.6,91.3,82.9,66.0,60.7,60.4,57.2,56.2 ppm. Mass Spectrometry data: HRMS (CI+) calculated for C18H20O6[ M]:332.1260,found: 332.1272.
Example 14: (R) -4- (7- (hydroxymethyl) - [1,3] dioxazole-6, 7-dihydronaphtho [4,5-f ] furan-7-yl) phenol
(R)-4-(7-(hydroxymethyl)-6,7-dihydro-[1,3]dioxolo[4,5-f]benzofuran-7-yl)phenol
To a solution of 3- (4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and benzodioxolan-5-ol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.045 mmol,15 mol%) followed by Sc (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at 0 ℃ for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) in 68% yield (58.2 mg), 93% ee, the compound was a transparent oil.
Nuclear magnetic data: 1 H NMR(300MHz,acetone-d6)δ8.25(s,1H),7.22-7.17(m,2H), 6.80-6.75(m,2H),6.67(s,1H),6.40(s,1H),5.92(s,2H),4.76(d,J＝8.7Hz,1H), 4.48(d,J＝9.0Hz,1H),4.05-4.00(m,3H). 13 c NMR (75 MHz, acetate-d 6) delta 156.4, 155.8,148.2,141.9,135.6,128.7,123.5,115.5,105.9,101.7,93.1,82.2,67.2,56.0 mass spectrometry data: HRMS (CI+) Calcd for C16H14O5[ M ]]:286.0841,Found:286.0837.
Example 15: (R) -4- (1- (hydroxymethyl) -1,2-dihydronaphtho [2,1-b ] furan-1-yl) -2, 6-bisphenol
(R)-4-(1-(Hydroxymethyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)-2,6-dimethylphenol
To a solution of 3- (3, 5-dimethyl-4-hydroxyphenyl) oxetan-3-ol (0.30 mmol) and 2-phenol (0.3 mmol) in DCM (6.0 mL) was added the catalyst CPA-V (0.03 mmol,10 mol%) followed by Sc (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) in 76% yield (73.2 mg), 95% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,acetone-d6)δ7.85-7.73(m,2H),7.52-7.43(m, 1H),7.26-7.12(m,4H),7.05(s,2H),5.04(d,J＝8.8Hz,1H),4.52(d,J＝8.8Hz, 1H),4.45(dd,J 1 ＝10.8Hz,J 2 ＝5.2Hz,1H),4.34(dd,J 1 ＝10.4Hz,J 2 ＝3.2Hz,1H), 4.30-4.12(m,1H),2.16(s,6H)ppm. 13 c NMR (75.5 MHz, acetone-d 6) delta 159.6, 152.6,136.1,131.8,130.9,130.8,129.7,128.1,126.7,124.5,123.9,123.2,123.1, 112.9,83.9,66.1,57.5,16.8ppm mass spectrometry data: HRMS (CI+) calculated for C21H20O 3[ M]:320.1412,found:320.1427.
Example 16: (R) - (1- (4- (benzyloxy) phenyl) -1, 2-dihydronaphthalene [2,1-b ] furan-1-yl) methanol
(R)-(1-(4-(Benzyloxy)phenyl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)methanol
To a solution of 3- (4-benzyloxyphenyl) oxetan-3-ol (0.30 mmol) and 2-phenol (0.3 mmol) in DCM (6.0 mL) was added catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that the dissolution of the end product in halogenated solvents is due toPoor quality, a cloudy solution is produced. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=7:1) in 59% yield (67.6 mg), 90% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,CDCl3)δ7.81(dd,J 1 ＝6.0Hz,J 1 ＝3.2Hz, 1H),7.78(d,J＝8.8Hz,1H),7.45-7.30(m,6H),7.28-7.23(m,4H),7.19(d,J＝8.8 Hz,1H),6.96-6.90(m,2H),5.03(s,2H),4.95(d,J＝8.8Hz,1H),4.58(d,J＝8.8Hz, 1H),4.49(dd,J 1 ＝11.2Hz,J 2 ＝3.6Hz,1H),4.30(dd,J 1 ＝10.8Hz,J 2 ＝8.4Hz,1H), 4.13(d,J＝10.4Hz,1H)ppm. 13 c NMR (100 mhz, cdcl 3) delta 159.4,157.6,136.8, 135.4,131.1,130.6,130.0,129.2,128.6,128.2,128.0,127.5,126.8,122.9,122.5, 119.5,115.0,112.5,83.4,70.0,66.4,57.1ppm mass spectral data: HRMS (CI+) calculated for C26H22O3[ M]:382.1569,found:382.1572.
Example 17: (R) - (1- (1-phenyl-1H-indol-3-yl) -1, 2-dihydronaphthalene [2,1-b ] furan-1-yl) methanol
(R)-(1-(1-Benzyl-1H-indol-3-yl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)methanol
To a solution of 3- (1-phenyl-1H-indol-3-yl) oxetan-3-ol (0.30 mmol) and 2-phenol (0.3 mmol) in DCM (6.0 mL) was added at room temperature the catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 24 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=6:1) in 84% (102.0 mg), 99% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,CDCl3)δ7.77(d,J＝8.4Hz,2H),7.59(d,J＝ 8.0Hz,1H),7.34-7.12(m,9H),7.11-7.04(m,3H),6.86(t,J＝7.6Hz,1H),5.32(s, 2H),4.99(d,J＝8.8Hz,1H),4.93(d,J＝8.8Hz,1H),4.52(d,J＝10.8Hz,1H),4.34 (d,J＝11.2Hz,1H)ppm. 13 c NMR (100 MHz, CDCl 3) delta 158.9,137.5,137.2,131.0, 130.9,129.8,129.1,128.8,127.6,126.54,126.50,126.4,125.6,122.7,122.0,121.8, 120.1,119.4,119.1,116.3,112.5,109.9,80.8,67.0,52.9,49.9ppm mass spectral data: HRMS (CI+) calculated for C28H23NO2[ M]:405.1729,found:405.1745.
Example 18: (R) - (1- (5-methylfuran) -1,2-dihydronaphtho [2,1-b ] furan-1-yl) methanol
(R)-(1-(5-Methylfuran-2-yl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)methanol
To a solution of 3- (5-methyl-furan-2-yl) oxetan-3-ol (0.30 mmol) and 2-phenol (0.3 mmol) in DCM (6.0 mL) was added catalyst CPA-V (0.03 mmol,10 mol%) followed by Yb (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 24 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=6:1) in 89% yield (74.6 mg), 92% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,CDCl3)δ7.80(d,J＝8.0Hz,1H),7.76(d,J＝ 8.8Hz,1H),7.61(d,J＝8.4Hz,1H),7.34(t,J＝7.2Hz,1H),7.27(t,J＝7.6Hz,1H), 7.16(d,J＝8.8Hz,1H),6.07(d,J＝2.8Hz,1H),5.93(s,1H),4.94(d,J＝8.8Hz, 1H),4.76(d,J＝8.8Hz,1H),4.37-4.22(m,2H),2.25(s,3H)ppm. 13 c NMR (100 MHz, CDCl 3) delta 158.8,153.2,151.8,131.1,130.7,129.9,129.1,126.8,122.9,122.0, 118.0,112.5,107.9,106.3,79.6,65.6,54.4,13.6ppm mass spectrometry data: HRMS (CI+) calculated for C18H16O3[ M]:280.1099,found:280.1107.
Example 19: (R) - (1- (5-methylthiophene) -1,2-dihydronaphtho [2,1-b ] furan-1-yl) methanol
(R)-(1-(5-methylthiophen-2-yl)-1,2-dihydronaphtho[2,1-b]furan-1-yl)methanol
To a solution of 3- (5-methyl-thiophen-2-yl) oxetan-3-ol (0.30 mmol) and 2-phenol (0.3 mmol) In DCM (6.0 mL) was added catalyst CPA-V (0.03 mmol,10 mol%) followed by In (OTf) at room temperature 3 (0.03 mmol,10 mol%). The reaction mixture was stirred at room temperature for 72 hours. It is worth mentioning that a cloudy solution is produced due to the poor solubility of the final product in halogenated solvents. The reaction mixture was diluted with ethyl acetate and concentrated, then the residue was purified directly by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=7:1) in 77% yield (68.6 mg), 93% ee, the compound was a white solid.
Nuclear magnetic data: 1 H NMR(400MHz,CDCl3)δ7.81(dd,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H), 7.78(d,J＝8.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.36-7.24(m,2H),7.16(d,J＝8.8 Hz,1H),6.70(d,J＝3.6Hz,1H),6.60(dd,J 1 ＝3.6Hz,J 2 ＝1.2Hz,1H),4.97(d,J＝ 8.8Hz,1H),4.64(d,J＝8.8Hz,1H),4.44(dd,J 1 ＝11.2Hz,J 2 ＝4.4Hz,1H),4.24 (dd,J 1 ＝11.2Hz,J 2 ＝8.4Hz,1H),2.42(d,J＝0.8Hz,3H)ppm. 13 c NMR (100 MHz, CDCl 3) delta 159.1,144.5,139.3,131.4,130.5,130.0,129.3,126.9,124.8,124.4,123.0, 122.3,118.9,112.5,83.0,66.9,55.7,15.3ppm mass spectrometry data: HRMS (CI+) calculated for C18H16O2S [ M]:296.0871,found:296.0870。

Claims (5)

1. A synthetic method of (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds is characterized in that: the synthesis method comprises the following steps: taking 3-aryl oxetane compounds (compound 1) and phenol compounds (compound 2) as raw materials, and CPA V and Lewis acid as catalysts, and reacting to obtain (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds;
the structure of CPA V is:
the Lewis acid catalyst is selected from In (OTf) 3 ,Yb(OTf) 3 ,Sc(OTf) 3 ,Cu(OTf) 2 One of the following;
Ar 1 any one selected from aryl, heteroaryl, substituted aryl and substituted heteroaryl; the aryl is selected from one of phenyl, naphthyl, phenanthryl, anthryl, acenaphthylenyl, fluorenyl, pyrenyl and fluoranthryl;
the heteroaryl is selected from one of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl and purinyl;
the substituents in the substituted aryl and substituted heteroaryl are each independently selected from one of fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, carboxy, alkyl, haloalkyl, alkoxy, alkylthio, alkenyl, alkynyl, nitro, mercapto, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, alkyl ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy, haloalkyloxy and cycloalkylalkyl;
Ar 2 any one selected from aryl groups and substituted aryl groups; the aryl is selected from one of phenyl, naphthyl, phenanthryl, anthryl, acenaphthylenyl, fluorenyl, pyrenyl and fluoranthryl; the substituents in the substituted aryl groups are each independently selected from fluorine, chlorine, bromine, iodine, cyano, hydroxyOne of a group, amino, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, alkenyl, alkynyl, nitro, mercapto, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, alkyl ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy, haloalkyloxy, and cycloalkylalkyl.
2. The method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds according to claim 1, wherein the method comprises the following steps: the synthesis reaction conditions are as follows: the reaction is carried out at room temperature or at 0 ℃ for 24 to 72 hours.
3. The method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds according to claim 1, wherein the method comprises the following steps: the molar ratio of the 3-aryl oxetane compound to the phenolic compound is 1:1 to 1:3.
4. the method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds according to claim 1, wherein the method comprises the following steps: the dosage of the chiral phosphoric acid catalyst CPA-V is 10-15mol% of the mole number of the compound 1 raw material.
5. The method for synthesizing (R) -3-phenyl-3-hydroxymethyl-2, 3-dihydrobenzofuran compounds according to claim 1, wherein the method comprises the following steps: the dosage of the Lewis acid catalyst is 10-15mol% of the mole number of the raw material of the compound 1.
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Publication number Priority date Publication date Assignee Title
CN110894192A (en) * 2019-10-17 2020-03-20 心远(广州)药物研究有限公司 Preparation method of benzofuran compound
CN113861169A (en) * 2021-10-22 2021-12-31 西华大学 Polysubstituted naphtho-dihydrofuran compound, preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110894192A (en) * 2019-10-17 2020-03-20 心远(广州)药物研究有限公司 Preparation method of benzofuran compound
CN113861169A (en) * 2021-10-22 2021-12-31 西华大学 Polysubstituted naphtho-dihydrofuran compound, preparation method and application thereof

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