CN114956929B - Synthesis method of chiral nitrile compound - Google Patents

Synthesis method of chiral nitrile compound Download PDF

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CN114956929B
CN114956929B CN202210522506.3A CN202210522506A CN114956929B CN 114956929 B CN114956929 B CN 114956929B CN 202210522506 A CN202210522506 A CN 202210522506A CN 114956929 B CN114956929 B CN 114956929B
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chiral
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chloroform
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CN114956929A (en
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陈加荣
张斌
宋禄彤
李凌涯
肖文精
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Central China Normal University
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Abstract

The invention relates to a synthesis method of chiral nitrile compounds, which comprises the following steps: under the protection of inert gas, in an organic solvent, under the existence of a photocatalyst Ph-PTZ, a copper catalyst, a chiral oxazoline ligand, TMSCN, water and ultraviolet lamp irradiation, the aryl vinyl compound is converted into the chiral aryl acetonitrile compound.

Description

Synthesis method of chiral nitrile compound
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of chiral nitrile compounds.
Background
Chiral nitrile compounds have wide application in synthetic chemistry and can be converted into carboxylic acid, amide, aldehyde, ketone compounds and some heterocyclic compounds under certain conditions. In addition, nitrile compounds have also been widely used in pharmaceutical chemistry, and are synthetic precursors for a number of drug molecules, for example, carboxylic acid compounds obtained by hydrolysis of nitrile compounds are structures of some common non-steroidal anti-inflammatory drugs. The synthesis of chiral nitriles and derivatives thereof has therefore attracted increasing research interest for organic and pharmaceutical chemists. In recent years, research on asymmetric cyanation reactions catalyzed by transition metals has been progressed, and problems such as severe reaction conditions or the need of adding additional hydrosilylation reagents and the like are faced, but no examples of asymmetric hydrocyanation of olefins by combining photocatalysis and copper catalysis have been reported.
Disclosure of Invention
The technical problems solved by the invention are as follows: the method uses N, N-dimethylacetamide as a solvent, uses olefin compounds as a substrate, uses water as a hydrogen source and TMSCN as a nitrile source, and prepares the chiral nitrile compound by synergistic catalysis of a photocatalyst, namely, phenyl thiothiazine (PC-I) and a copper catalyst under ultraviolet light.
The specific solution provided by the invention is as follows:
the invention provides a synthesis method of chiral nitrile compounds, which comprises the following steps: under the protection of inert gas, converting the aryl vinyl compound into chiral aryl acetonitrile compound in an organic solvent in the presence of a photocatalyst Ph-PTZ, a copper catalyst, a chiral oxazoline ligand, trimethylcyanosilane TMSCN, water and ultraviolet lamp irradiation.
(1) According to the method, N-dimethylacetamide is used as a solvent, olefin compounds are used as a substrate, water is used as a hydrogen source, trimethylcyano silane TMSCN is used as a nitrile source, under ultraviolet light, a photocatalyst 10-phenylphenol thiazine (Ph-PTZ) and a copper catalyst are used for preparing the chiral nitrile compounds through synergistic catalysis, and the method is mild in reaction condition, simple in synthetic route and efficient in preparation method.
(2) The visible light is used as a safe, clean and green energy source, the asymmetric hydrocyanation reaction of the olefin is realized by a green and efficient method, a series of chiral medicaments, such as chiral flurbiprofen axetil and other anti-inflammatory medicaments, can be synthesized by derivative application of the obtained chiral nitrile compounds, a new way is provided for synthesizing the medicaments, and the synthetic route of the medicaments is greatly shortened.
Based on the scheme, the invention can also be improved as follows:
preferably, the chiral oxazoline ligand is selected from one or more of the following structures:
more preferably, the chiral oxazoline ligand is selected from one of L1, L2 or L6:
the three ligands L1, L2 and L6 are selected as chiral ligands, and compared with L3, L4 and L5, the product shown in the formula II has higher yield and higher enantioselectivity.
Preferably, the copper catalyst is selected from [ Cu (MeCN) 4 ]PF 6 CuTc, cuBr, cuCl, cu (OAc), cuSCN, cu (OTf) or Cu (OTf) 2 One or more of the following.
Preferably, the organic solvent is selected from one or more of N, N-dimethylacetamide, acetonitrile or methanol, preferably, the organic solvent is DMA. In contrast, DMA is used as a solvent, and the yield of the product is high and the enantioselectivity is high.
Preferably, the ratio of the amounts of the copper catalyst, the chiral oxazoline ligand, the photocatalyst Ph-PTZ, TMSCN, the olefin compound shown in the formula I and water is (1% -3%): (2% -4%): (8% -12%): (1-2): (0.5-1.5): (0.5-1.5).
Preferably, in the process of converting the aryl vinyl compound into the chiral aryl acrylonitrile compound, the reaction progress is monitored by TLC, after the reaction is finished, diluted reaction liquid is added, ethyl acetate is used for extraction, and the organic phase is dried by anhydrous sulfuric acid and then subjected to column chromatography to obtain the chiral nitrile compound.
Preferably, a silica gel column is adopted in the column chromatography, and petroleum ether-ethyl acetate with the volume ratio of 40:1 to 20:1 is adopted as an eluent for gradient elution, so that the chiral aryl acetonitrile compound is obtained.
Preferably, the following reaction formula for converting the styrene compound into the chiral benzyl cyanide compound shows that the olefin compound is shown as a formula I-a, a formula I-b or a formula I-c, and the chiral nitrile compound is shown as a formula II-a, a formula II-b or a formula II-c:
in each reaction formula, ring a is aryl or heteroaryl;
the R is 1 、R 2 、R 3 The structure of (2) is selected as follows:
R 2 or R is 3 One of which is H and the other is cyano, ester or alkenyl, said R 1 Is a single substituent or multiple substituents, and each substituent in the single substituent and the multiple substituents is independently selected from one of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted double bond, substituted or unsubstituted triple bond and cyano;
alternatively, the R 2 Or R is 3 One of them is H and the other is alkyl, or R 2 And R is R 3 A cyclic, ring system 3 membered carbocyclic ring, said R 1 Is a single substituent or multiple substituents, and each substituent in the single substituent and the multiple substituents is independently selected from one of substituted or unsubstituted aryl, substituted or unsubstituted double bond, substituted or unsubstituted triple bond, or cyano;
alternatively, R 2 Is H, said R 1 And R is R 3 Forming a ring, wherein the ring system is a 6-membered alicyclic ring;
the R is 4 、R 5 The structure of (2) is selected as follows:
R 4 one selected from halogen, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted triple bond and cyano, and two R in the same structure 4 The substitution sites on ring A are the same;
R 5 one selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted double bond, a substituted or unsubstituted triple bond, or a cyano group.
Thus, the styrene compound (such as aromatic ring, heteroaromatic ring, double bond, triple bond, acetonitrile or ethyl ester) with a main structure containing a larger conjugated system is reacted to obtain chiral aryl acetonitrile with high yield and high enantioselectivity.
More preferably, the aryl vinyl compound is selected from one of the following structures:
the chiral aryl acetonitrile compound is selected from one of the following structures:
additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following detailed description of embodiments of the invention is exemplary and intended to be illustrative of the invention and not to be construed as limiting the invention.
Example 1
Preparation of Compound II-1
Thiophene-2-carboxylic acid cuprous CuTc (0.0048 mmol,2 mol%) and ligand (0.0048 mmol,2.4 mol%) were dissolved in 4mL of DMA at room temperature and stirred under argon for 1 hour. Subsequently Ph-PTZ (0.02 mmol,10 mol%), TMSCN (0.3 mmol,1.5 equiv.) and water (0.2 mmol,1.0 equiv.) are added, the reaction mixture is reacted under 20W violet light until the TLC detection reaction is complete, then 50ml water is added for dilution, extraction four times with 20ml ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and column chromatography is carried out directly on V petroleum ether/V ethyl acetate=40:1-20:1 to give the desired product of formula II-1.
Compound II-1Prepared from alkene I-1 AS substrate in 93% yield, 92% enantiomeric excess (ee) (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v: v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.48min,t R (major)＝15.02min. 1 H NMR(400MHz,Chloroform-d)δppm 7.62–7.57(m,4H),7.47–7.35(m,5H),3.95(q,J＝7.2Hz,1H),1.68(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 13C NMR(101MHz,Chloroform-d)δ141.06,140.22,135.95,128.84,127.82,127.58,127.13,127.06,121.54,30.92,21.43.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 13 NNa:230.0946,found:230.0936.
Example 2
Preparation of Compound II-2
The procedure is as in example 1, except that compound II-2From olefins I-2And (5) preparing a substrate.
The yield of the product was 64%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.43min,t R (major)＝11.94min. 1 H NMR(400MHz,Chloroform-d)δppm 7.62–7.57(m,2H),7.49–7.40(m,4H),7.27–7.25(m,2H),3.93(q,J＝7.6Hz,1H),2.40(s,3H),1.67(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 140.97,137.43,137.32,135.63,129.56,127.59,127.08,126.88,30.90,21.42,21.09.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 15 NNa:244.1102,found:244.1112.
Example 3
Preparation of Compound II-3
The procedure is as in example 1, except that compound II-3Is prepared by taking alkene I-3 as a substrate.
The yield of the product was 73%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.62min,t R (major)＝10.83min. 1 H NMR(400MHz,Chloroform-d)δppm 7.61–7.40(m,8H),3.94(q,J＝7.2Hz,1H),1.68(d,J＝7.2Hz,3H),1.36(s,9H). 13 C NMR(100MHz,Chloroform-d)δ150.64,140.88,135.62,127.65,127.08,126.70,125.80,121.59,34.53,31.31,30.91,21.41.HRMS(ESI):m/z[M+Na]+calcd for C 19 H 21 NNa:286.1572,found:286.1553.
Example 4
Preparation of Compound II-4
The procedure is as in example 1, except that compound II-4Prepared by taking alkene I-4 as a substrate.
The yield of the product was 86%, the enantiomeric excess was 85% (determined by chiral HPLC; HPLC fractions)The chromatographic chiral AZ-H column, isopropanol/n-hexane 90:10, v:v), 0.8mL/min,254nm,25 ℃ and retention time t R (minor)＝34.68min,t R (major)＝37.83min. 1 H NMR(400MHz,Chloroform-d)δppm 7.58–7.56(m,4H),7.43–7.41(m,2H),7.18–7.16(m,2H),3.94(q,J＝7.6Hz,1H),2.33(s,3H),1.67(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 169.53,150.26,140.17,137.97,136.07,128.10,127.76,127.17,121.96,121.48,30.88,21.37,21.12.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 15 NNaO 2 :288.1000,found:288.0988.
Example 5
Preparation of Compound II-5
The procedure is as in example 1, except that compound II-5Prepared by taking alkene I-5 as a substrate.
The yield of the product was 71%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝17.58min,t R (major)＝20.80min. 1 H NMR(400MHz,Chloroform-d)δppm 7.56–7.51(m,4H),7.43–7.41(m,2H),7.15–7.10(m,2H),3.94(q,J＝7.2Hz,1H),1.67(dd,J＝7.6,1.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 163.79,161.33,140.04,136.31,135.99,128.62(d,J＝8.0Hz),127.66,127.18,121.49,115.82,115.61,30.87,21.38. 19 F NMR(376MHz,Chloroform-d)δppm-115.10.HRMS(ESI):m/z[M+Na]+calcd for C15H12FNNa:248.0851,found:248.0850.
Example 6
Preparation of Compound II-6
The procedure is as in example 1, except that compound II-6Is prepared by taking alkene I-6 as a substrate.
The yield of the product was 53%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed by hand)Sex AS-H column, isopropanol/n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃with retention time t R (minor)＝14.33min,t R (major)＝15.60min. 1 H NMR(400MHz,Chloroform-d)δppm 7.72–7.46(m,8H),3.97(q,J＝7.2Hz,1H),1.69(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm143.71,139.59,137.01,129.62(q,J＝32.5Hz),127.99,127.37,127.35,125.79(q,J＝3.7Hz),124.17(q,J＝270Hz)121.35,30.94,21.38. 19 F NMR(376MHz,Chloroform-d)δppm-62.42.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 12 F 3 N:275.0922,found:275.0914.
Example 7
Preparation of Compound II-7
The procedure is as in example 1, except that compound II-7Prepared by taking alkene I-7 as a substrate.
The yield of the product was 82%, the enantiomeric excess was 89% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.00min,t R (major)＝11.59min. 1 H NMR(400MHz,Chloroform-d)δppm 7.92–7.84(m,3H),7.54–7.38(m,8H),3.99(q,J＝7.6Hz,1H),1.73(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 140.60,139.22,135.95,133.73,131.40,130.75,128.32,127.90,126.92,126.65,126.17,125.85,125.70,125.33,121.61,31.03,21.41.HRMS(ESI):m/z[M+Na] + calcd for C 19 H 15 NNa:280.1102,found:280.1092.
Example 8
Preparation of Compound II-8
The procedure is as in example 1, except that compound II-8Is prepared by taking alkene I-8 as a substrate.
The yield of the product was 91% and the enantiomeric excess was 92% (determined by chiral HPLC; chiral HPLC analysis)AS-H column, isopropanol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃with retention time t R (minor)＝15.32min,t R (major)＝19.08min. 1 H NMR(400MHz,Chloroform-d)δppm 7.60–7.58(m,2H),7.46–7.44(m,1H),7.40–7.36(m,4H),3.91(q,J＝7.2Hz,1H),1.65(d,J＝7.6Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 141.27,135.66,135.56,127.12,127.00,126.44,126.10,121.51,120.65,30.84,21.33.HRMS(ESI):m/z[M+Na]+calcd for C 13 H 11 NNaS:236.0510,found:236.0501.
Example 9
Preparation of Compound II-9
The procedure is as in example 1, except that compound II-9Is prepared by taking alkene I-9 as a substrate.
The yield of the product was 47%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝20.57min,t R (major)＝24.85min. 1 H NMR(400MHz,Chloroform-d)δppm 7.63–7.60(m,2H),7.37–7.29(m,4H),7.10–7.08(m,1H),3.91(q,J＝7.2Hz,1H),1.66(d,J＝7.2Hz,3H). 13 CNMR(100MHz,Chloroform-d)δ143.31,136.02,134.25,128.11,127.24,126.53,125.22,123.48,30.90,21.35.HRMS(ESI):m/z[M+Na]+calcd for C 13 H 11 NNaS:236.0510,found:236.0503.
Example 10
Preparation of Compound II-10
The procedure is as in example 1, except that compound II-10Is prepared by taking alkene I-10 as a substrate.
The yield of the product was 70%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝11.61min,t R (major)＝12.78min. 1 H NMR(400MHz,Chloroform-d)δppm 7.57–7.32(m,8H),4.06(q,J＝7.2Hz,1H),2.41(s,3H),1.63(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 141.01,140.26,135.15,134.19,129.67,128.76,127.47,127.15,127.00,125.58,121.70,27.90,19.97,19.13.HRMS(ESI):m/z[M+Na]+calcd for C16H15NNa:244.1102,found:244.1098.
Example 11
Preparation of Compound II-11
The procedure is as in example 1, except that compound II-11Prepared by taking alkene I-11 as a substrate.
The yield of the product was 45%, the enantiomeric excess was 87% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.36min,t R (major)＝13.50min. 1 H NMR(400MHz,Chloroform-d)δppm 7.59–7.35(m,6H),7.22–7.08(m,2H),4.28(q,J＝7.2Hz,1H),3.93(s,3H),1.61(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 156.26,142.74,140.67,128.82,127.90,127.67,127.14,124.32,121.95,119.77,109.69,55.53,25.44,19.50.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 15 NNaO:260.1051,found:260.1046.
Example 12
Preparation of Compound II-12
The procedure is as in example 1, except that compound II-12Is prepared by taking alkene I-12 as a substrate.
The yield of the product was 77%, the enantiomeric excess was 95% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.10min,t R (major)＝9.80min. 1 H NMR(400MHz,Chloroform-d)δppm 7.57–7.38(m,7H),7.32(dd,J＝11.6,2.0Hz,1H),4.22(q,J＝7.2Hz,1H),1.67(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 159.90(d,J＝246.1Hz),143.56(d,J＝7.9Hz),139.06,128.97,128.56(d,J＝3.8Hz),128.16,126.98,123.37(d,J＝3.2Hz),120.70,114.38(d,J＝22.0Hz),25.18(d,J＝3.4Hz),20.09.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 12 FNNa:248.0851,found:248.0846.
Example 13
Preparation of Compound II-13
The procedure is as in example 1, except that compound II-13Prepared by taking alkene I-13 as a substrate.
The yield of the product was 40%, the enantiomeric excess was 92% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.05min,t R (major)＝8.82min. 1 H NMR(400MHz,Chloroform-d)δppm 7.70–7.58(m,4H),7.48–7.41(m,6H),7.37–7.32(m,3H),4.04(q,J＝7.2Hz,1H),1.51(d,J＝7.2Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 141.49,140.93,140.06,140.00,134.06,129.26,129.09,128.95,128.77,127.91,127.79,127.70,127.19,127.16,122.34,27.76,21.45.HRMS(ESI):m/z[M+Na]+calcd for C 21 H 17 NNa:306.1259,found:306.1246.
Example 14
Preparation of Compound II-14
The procedure is as in example 1, except that compound II-14Prepared by taking alkene I-14 as a substrate.
The yield of the product was 59%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AD-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.54min,t R (major)＝10.33min. 1 H NMR(400MHz,Chloroform-d)δppm 7.51–7.47(m,2H),7.42–7.30(m,4H),7.00–6.95(m,2H),3.92(q,J＝7.2Hz,1H),3.83(s,3H),1.69(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 156.85,137.65,137.48,131.39,130.48,129.39,128.02,127.16,121.53,118.98,109.54,55.62,31.22,21.40.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 15 NNaO:260.1051,found:260.1046.
Example 15
Preparation of Compound II-15
The procedure is as in example 1, except that compound II-15Prepared by taking alkene I-15 as a substrate.
The yield of the product was 92%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.17min,t R (major)＝15.78min. 1 H NMR(400MHz,Chloroform-d)δppm 7.54–7.52(m,2H),7.48–7.37(m,4H),7.25–7.16(m,2H),3.94(q,J＝7.2Hz,1H),1.68(d,J＝7.2Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 159.76(d,J＝248.4Hz),138.07(d,J＝7.5Hz),134.89,131.46(d,J＝3.9Hz),128.89(d,J＝3.0Hz),128.52,127.96,122.68(d,J＝3.5Hz),120.98,114.66(d,J＝24.4Hz),30.70,21.16. 19 F NMR(376MHz,Chloroform-d)δ-116.30.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 12 FNNa:248.0851,found:248.0859.
Example 16
Preparation of Compound II-16
The procedure is as in example 1, except that compound II-16Prepared by taking alkene I-16 as a substrate.
The yield of the product was 48%, the enantiomeric excess was 82%, (determined by chiral HPLC; HPLC analysis using a chiral AS-H column, isopropyl alcohol: n-hexane 95:5, v: v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.83min,t R (major)＝13.08min. 1 H NMR(400MHz,Chloroform-d)δppm 7.61–7.57(m,4H),7.47–7.34(m,5H),3.79(t,J＝7.2Hz,1H),1.99(p,J＝7.6Hz,2H),1.11(t,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 141.01,140.26,134.67,128.85,127.71,127.58,127.07,120.71,38.59,29.18,11.51.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 15 NNa:244.1102,found:244.1106.
Example 17
Preparation of Compound II-17
The preparation procedure is as in example 1, except for II-17Prepared by taking alkene I-17 as a substrate.
The yield of the product was 48%, the enantiomeric excess was 72% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.25min,t R (major)＝12.13min. 1 H NMR(400MHz,Chloroform-d)δppm 7.62–7.57(m,4H),7.47–7.34(m,5H),3.53(d,J＝7.6Hz,1H),1.37–1.28(m,1H),0.79–0.67(m,2H),0.62–0.49(m,2H). 13 C NMR(100MHz,Chloroform-d)δppm 141.12,140.22,134.46,128.82,127.72,127.66,127.55,127.04,119.78,40.66,15.49,4.80,3.89.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 15 NNa:256.1102,found:256.1096.
Example 18
Preparation of Compound II-18
The procedure is as in example 1, except that compound II-18Prepared by taking alkene I-18 as a substrate.
The yield of the product was 70%, the enantiomeric excess was 92% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 99:1, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝17.54min,t R (major)＝16.20min. 1 H NMR(400MHz,Chloroform-d)δppm 7.94–7.83(m,3H),7.70–7.68(m,1H),7.60–7.47(m,3H),4.62(q,J＝7.2Hz,1H),1.78(d,J＝7.6Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 133.98,132.63,129.77,129.28,128.92,126.90,126.09,125.53,124.67,122.04,121.77,28.21,20.53.HRMS(ESI):m/z[M+H]+calcd for C 13 H 12 N:182.0970,found:182.0966.
Example 19
Preparation of Compound II-19
The preparation procedure is as in example 1, except that compound II-19Prepared by taking alkene I-19 as a substrate.
The yield of the product was 58%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis using a chiral AD-H column with isopropyl alcohol: n-hexane 95:5, v: v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝20.07min,t R (major)＝21.85min. 1 H NMR(400MHz,Chloroform-d)δppm 7.88–7.83(m,4H),7.54–7.48(m,2H),7.44–7.42(m,1H),4.07(q,J＝7.3Hz,1H),1.73(d,J＝7.6Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 134.29,133.30,132.76,129.13,127.83,127.70,126.71,126.47,125.56,124.38,121.56,31.40,21.41.HRMS(ESI):m/z[M+Na]+calcd for C 13 H 11 NNa:204.9789,found:204.0781.
Example 20
Preparation of Compound II-20
The procedure is as in example 1, except that compound II-20Is prepared by taking alkene I-20 as a substrate.
The yield of the product was 72%, the enantiomeric excess was 89% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝22.09min,t R (major)＝20.06min. 1 H NMR(400MHz,Chloroform-d)δppm 8.79–8.66(m,1H),7.98–7.91(m,3H),7.73–7.61(m,4H),4.65(q,J＝7.2Hz,1H),1.85(d,J＝7.2Hz,3H). 13 CNMR(100MHz,Chloroform-d)δppm 131.03,130.87,130.19,128.78,128.56,127.35,127.18,127.16,126.88,125.78,123.75,122.82,122.48,121.75,28.52,20.29.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 13 NNa:254.0946,found:254.0952.
Example 21
Preparation of Compound II-21
The procedure is as in example 1, except that compound II-21Prepared from alkene I-21 as substrate using acetonitrile as solvent.
The yield of the product was 65%, the enantiomeric excess was 87% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝11.06min,t R (major)＝12.10min. 1 H NMR(400MHz,Chloroform-d)δppm 7.39–7.27(m,5H),6.72(d,J＝15.6Hz,1H),6.07(dd,J＝16.0,6.0Hz,1H),3.51(p,J＝6.9Hz,1H),1.51(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 135.66,132.53,128.70,128.25,126.52,124.27,120.86,28.36,19.03.HRMS(ESI):m/z[M+Na]+calcd for C 11 H 12 N:158.0970,found:158.0969.
Example 22
Preparation of Compound II-22
The procedure is as in example 1, except that compound II-22Prepared by taking alkene I-22 as a substrate.
The yield of the product was 96%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝25.61min,t R (major)＝17.95min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.38–7.25(m,8H),7.15–7.13(m,2H),4.00(dd,J＝8.4,6.4Hz,1H),3.16(qd,J＝13.6,7.4Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.24,135.18,129.19,128.99,128.60,128.18,127.46,127.36,42.17,39.78.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 13 NNa:230.0946,found:230.0944.
Example 23
Preparation of Compound II-23
The procedure is as in example 1, except that compound II-23Prepared by taking alkene I-23 as a substrate.
The yield of the product was 85%, the enantiomeric excess was 83% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝10.39min,t R (major)＝11.05min. 1 H NMR(400MHz,Chloroform-d)δppm 7.15–7.02(m,8H),3.92(dd,J＝8.4,6.4Hz,1H),3.14–3.03(m,1H),2.33(d,J＝9.6Hz,6H). 13 C NMR(100MHz,Chloroform-d)δppm 137.89,136.88,133.34,132.30,129.60,129.24,129.02,127.28,120.59,41.81,39.54,21.04.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 17 NNa:258.1259,found:258.1255.
Example 24
Preparation of Compound II-24
The procedure is as in example 1, except that compound II-24Prepared by taking alkene I-24 as a substrate.
The product yield was 76%, enantiomeric excess was 88% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝17.73min,t R (major)＝11.85min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.25–7.05(m,6H),6.97–6.94(m,2H),3.92(dd,J＝8.8,6.4Hz,1H),3.13–3.02(m,2H),2.32(d,J＝10.4Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)138.75,138.14,136.34,135.27,129.85,128.81,128.78,128.41,128.01,126.10,124.41,120.46,42.16,39.78,21.27.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 17 NNa:258.1259,found:258.1248.
Example 25
Preparation of Compound II-25
The procedure is as in example 1, except that compound II-25Prepared by taking alkene I-25 as a substrate.
The product yield was 78%, the enantiomeric excess was 81% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝13.26min,t R (major)＝11.50min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.48–7.45(m,1H),7.28–7.21(m,2H),7.18–7.09(m,5H),4.16(dd,J＝8.8,6.4Hz,1H),3.27–3.05(m,2H),2.25(s,3H),2.20(s,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.28,135.15,134.68,133.87,130.88,130.56,130.07,128.24,127.78,127.51,126.94,126.24,120.83,38.09,35.15,19.26,19.00.HRMS(ESI):m/z[M+Na]+calcd for C 17 H 17 NNa:258.1259,found:258.1248.
Example 26
Preparation of Compound II-26
The procedure is as in example 1, except that compound II-26Prepared by taking alkene I-26 as a substrate.
The product yield was 94%, enantiomeric excess was 88% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝22.00min,t R (major)＝14.95min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.20–7.17(m,2H),7.06–6.95(m,6H),3.97(t,J＝7.2Hz,1H),3.18–3.07(m,2H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)154.12,131.02,130.31,129.34,129.06,127.25,123.71,122.16(d,J＝6.3Hz),117.32,113.27,56.54,21.62,18.45. 19 F NMR(376MHz,Chloroform-d)δ(ppm)-113.28,-114.82.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 11 F 2 NNa:266.0758,found:266.0759.
Example 27
Preparation of Compound II-27
The procedure is as in example 1, except that compound II-27Prepared by taking alkene I-27 as a substrate.
The yield of the product was 50%, the enantiomeric excess was 94% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝25.95min,t R (major)＝22.01min. 1 H NMR(400MHz,Chloroform-d)δ7.29–7.19(m,2H),7.03–6.91(m,4H),4.32(t,J＝7.1Hz,1H),3.47(qd,J＝14.7,7.2Hz,2H). 13 C NMR(100MHz,Chloroform-d)δppm 137.34,136.42,127.16,127.10,126.75,125.89,125.11,119.19,36.25,35.15.HRMS(ESI):m/z[M+Na]+calcd for C 11 H 9 NS 2 Na:242.0074,found:242.0064.
Example 29
Preparation of Compound II-29
The procedure is as in example 1, except that compound II-29Prepared by taking alkene I-29 as a substrate.
The yield of the product was 91%, the enantiomeric excess was 85% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 80:20, v:v), 0.8mL/min,210nm,25℃and retention time t R (minor)＝36.40min,t R (major)＝33.34min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)1H NMR(400MHz,Chloroform-d)δ7.52–7.44(m,5H),4.22(t,J＝6.8Hz,1H),3.01(dd,J＝6.8,2.8Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)132.12,129.61,129.48,127.17,117.81,115.27,33.91,24.63.HRMS(ESI):m/z[M+Na]+calcd for C 10 H 8 N 2 Na:179.0585,found:179.0575.
Example 30
Preparation of Compound II-30
The procedure is as in example 1, except that compound II-30Prepared by taking alkene I-30 as a substrate.
The yield of the product was 86%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,210nm,25℃and retention time t R (minor)＝18.83min,t R (major)＝20.46min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.41–7.32(m,5H),4.30(dd,J＝8.2,6.6Hz,1H),3.71(s,3H),3.02(dd,J＝16.6,8.3Hz,1H),2.85(dd,J＝16.6,6.7Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)169.55,134.36,129.24,128.53,127.26,119.83,52.26,39.76,33.10.HRMS(ESI):m/z[M+Na]+calcd for C 11 H 11 NO 2 :212.0688,found:212.0686.
Example 31
Preparation of Compound II-31
The preparation procedure is as in example 1, except that compound II-31Prepared by taking alkene I-31 as a substrate.
The yield of the product was 70%, the enantiomeric excess was 64% (determined by chiral HPLC; HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝41.15min,t R (major)＝44.42min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.53–7.42(m,2H),7.29–7.25(m,1H),7.16–7.14(m,1H),4.33(dd,J＝10.8,5.2Hz,1H),3.22(dd,J＝16.0,5.4Hz,1H),3.08(dd,J＝16.2,10.9Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)163.90,150.76,130.86,127.06,125.51,117.83,116.93,116.39,32.32,27.08.HRMS(ESI):m/z[M+Na]+calcd for C 10 H 7 NO 2 :196.0375,found:196.0377.
Example 32
Preparation of Compound II-32
The procedure is as in example 1, except that compound II-32Prepared by taking alkene I-32 as a substrate.
The yield of the product was 57%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝6.12min,t R (major)＝7.62min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.41–7.39(m,2H),7.28–7.26(m,2H),3.88(q,J＝7.2Hz,1H),2.40(t,J＝7.0Hz,2H),1.63–1.56(m,4H),1.48–1.40(m,2H),1.33–1.27(m,9H),0.90–0.87(m,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.07,132.20,126.55,124.05,121.28,91.42,79.74,31.81,31.04,29.17,29.08,28.89,28.63,22.63,21.30,19.36,14.09.HRMS(ESI):m/z[M+Na]+calcd for C 19 H 25 NNa:290.1885,found:290.1880.
Example 33
Preparation of Compound II-33
The procedure is as in example 1, except that compound II-33Prepared by taking alkene I-33 as a substrate.
The yield of the product was 63%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝8.56min,t R (major)＝11.43min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.41–7.38(m,2H),7.28–7.25(m,2H),3.88(q,J＝7.2Hz,1H),2.41(t,J＝7.0Hz,2H),1.63–1.56(m,5H),1.52–1.43(m,2H),0.95(t,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.07,126.56,124.03,121.30,91.35,79.73,31.04,30.70,21.98,19.06,13.62.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 17 NNa:234.1259,found:234.1257.
Example 34
Preparation of Compound II-34
The procedure is as in example 1, except that compound II-34Prepared by taking alkene I-34 as a substrate.
The yield of the product was 81%, the enantiomeric excess was 92% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝7.89min,t R (major)＝14.17min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.39–7.37(m,2H),7.26–7.24(m,2H),3.87(q,J＝7.2Hz,1H),1.61(d,J＝7.6Hz,3H),1.45(tt,J＝8.4,5.2Hz,1H),0.90–0.78(m,4H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.05,132.23,126.54,123.87,121.26,94.32,74.95,31.02,21.25,8.59,0.09.HRMS(ESI):m/z[M+Na]+calcd for C 14 H 13 NNa:218.0946,found:218.0966.
Example 35
Preparation of Compound II-35
The procedure is as in example 1, except that compound II-35Is prepared by taking alkene I-35 as a substrate.
The yield of the product was 69%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral OD-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.79min,t R (major)＝11.02min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.42–7.40(m,2H),7.29–7.26(m,2H),3.89(q,J＝7.3Hz,1H),3.71(t,J＝6.2Hz,2H),2.61(t,J＝6.8Hz,2H),2.06(p,J＝6.6Hz,2H),1.63(d,J＝7.2Hz,3 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.44,132.24,126.62,123.48,121.22,88.98,80.68,43.67,31.27,31.03,21.27,16.79.HRMS(ESI):m/z[M+Na]+calcd for C 14 H 14 ClNNa:254.0713,found:254.0715.
Example 36
Preparation of Compound II-36
The procedure is as in example 1, except that compound II-36Prepared by taking alkene I-36 as a substrate.
The yield of the product was 53%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral OD-H column with isopropyl alcohol: n-hexane 80:20, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.14min,t R (major)＝18.08min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.44–7.41(m,2H),7.29–7.27(m,2H),3.89(q,J＝7.3Hz,1H),3.82(t,J＝6.4Hz,2H),2.69(t,J＝6.4Hz,2H),2.00(s,1H),1.63(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.59,132.34,126.63,123.30,121.19,87.32,81.57,61.03,31.03,23.75,21.23.HRMS(ESI):m/z[M+Na]+calcd for C 13 H 13 NONa:222.0895,found:222.0907.
Example 37
Preparation of Compound II-37
The procedure is as in example 1, except that compound II-37Prepared by taking alkene I-37 as a substrate.
The yield of the product was 62%, the enantiomeric excess was 91% (determined by chiral HPLC; HPLC analysis was performed using a chiral OD-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝27.75min,t R (major)＝31.59min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.41–7.39(m,2H),7.28–7.26(m,2H),3.88(q,J＝7.2Hz,1H),3.81(t,J＝6.2Hz,2H),2.54(t,J＝7.0Hz,2H),1.86(p,J＝6.6Hz,2H),1.81(s,1H),1.62(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.27,132.19,126.58,123.65,121.23,90.27,80.24,61.60,31.23,30.99,21.22,15.89.HRMS(ESI):m/z[M+Na]+calcd for C 14 H 15 NONa:236.1052,found:236.1053.
Example 38
Preparation of Compound II-38
The procedure is as in example 1, except that compound II-38Prepared by taking alkene I-38 as a substrate.
The yield of the product was 50%, the enantiomeric excess was 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝12.73min,t R (major)＝31.02min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.56–7.52(m,4H),7.37–7.33(m,5H),3.91(q,J＝7.3Hz,1H),1.65(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.94,132.29,131.62,128.46,128.37,126.76,123.26,122.94,121.17,90.14,88.48,31.13,21.28.HRMS(ESI):m/z[M+H]+calcd for C 17 H 14 N:232.1126,found:232.1128.
Example 39
Preparation of Compound II-39
The procedure is as in example 1, except that compound II-39Prepared by taking alkene I-39 as a substrate.
The yield of the product was 80%, the enantiomeric excess was 92% (determined by chiral HPLC; HPLC analysis was performed using a chiral OD-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝21.35min,t R (major)＝20.01min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.54–7.51(m,3H),7.34–7.19(m,4H),3.90(q,J＝7.3Hz,1H),1.64(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.85,132.16,129.78,128.89,126.74,125.47,123.14,121.93,121.17,88.01,85.26,31.09,21.25.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 11 NSNa:260.0510,found:260.0519.
Example 40
Preparation of Compound II-40
The preparation steps are the same as those of the solidExample 1, except that Compound II-40Prepared by taking alkene I-40 as a substrate.
The yield of the product was 71%, the enantiomeric excess was 93% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝14.10min,t R (major)＝16.38min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.42(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),6.71(dd,J＝17.6,10.8Hz,1H),5.76(d,J＝17.6Hz,1H),5.28(d,J＝11.2Hz,1H),3.89(q,J＝7.3Hz,1H),1.63(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)137.45,136.39,135.93,126.87,121.46,114.65,30.95,21.36.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 13 NNa:180.0789,found:180.0784.
Example 41
Preparation of Compound II-41
The procedure is as in example 1, except that compound II-41Prepared by taking alkene I-41 as a substrate.
The yield of the product was 42%, the enantiomeric excess was 85% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝6.51min,t R (major)＝7.37min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.30–7.22(m,4H),6.24(s,1H),3.88(q,J＝7.2Hz,1H),1.91(s,3H),1.86(s,3H),1.64(d,J＝7.2Hz,3H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)138.52,136.39,134.24,129.36,126.37,124.23,121.69,30.90,26.87,21.37,19.37.HRMS(ESI):m/z[M+H]+calcd for C 13 H 16 N:186.1282,found:186.1267.
Example 42
Preparation of Compound II-42
The procedure is as in example 1, except that compound II-42Prepared by taking alkene I-42 as a substrate.
The yield of the product was 85%, the enantiomeric excess was 83% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 80:20, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝15.62min,t R (major)＝14.49min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.71(d,J＝8.0Hz,2H),7.51(d,J＝8.0Hz,2H),3.99(q,J＝7.3Hz,1H),1.68(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)142.04,132.97,127.61,120.29,118.10,112.25,31.29,21.12.HRMS(ESI):m/z[M+H]+calcd for C 10 H 9 N 2 :157.0765,found:157.0755.
Example 43
Preparation of Compound II-43
The procedure is as in example 1, except that compound II-43Prepared by taking alkene I-43 as a substrate.
The yield of the product was 79%, the enantiomeric excess was 84% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝43.43min,t R (major)＝37.67min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)1H NMR(400MHz,Chloroform-d)δ7.67–7.63(m,3H),7.56–7.52(m,1H),3.98(q,J＝7.4Hz,1H),1.68(d,J＝7.5Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)138.47,131.83,131.19,130.29,130.10,120.35,118.01,113.36,30.86,21.12.HRMS(ESI):m/z[M+Na]+calcd for C 10 H 8 N 2 Na:179.0585,found:179.0578.
Example 44
Preparation of Compound II-44
The procedure is as in example 1, except that compound II-44From olefinsI-44 is a substrate preparation.
The yield of the product was 73%, the enantiomeric excess was 96% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝17.99min,t R (major)＝14.90min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.74–7.67(m,3H),7.50–7.46(m,1H),4.33(q,J＝7.2Hz,1H),1.72(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)140.68,133.88,133.40,128.78,127.63,120.00,116.52,111.18,30.18,21.24.HRMS(ESI):m/z[M+Na]+calcd for C 10 H 8 N 2 Na:179.0585,found:179.0581.
Example 45
Preparation of Compound II-45
The procedure is as in example 1, except that compound II-45Prepared by taking alkene I-45 as a substrate.
The yield of the product was 74%, the enantiomeric excess was 93% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝16.12min,t R (major)＝13.67min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.63–7.51(m,3H),4.31(q,J＝7.2Hz,1H),2.44(s,3H),1.72(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)139.10,137.66,134.65,133.59,127.44,120.18,116.68,110.88,29.73,21.23,20.70.HRMS(ESI):m/z[M+Na]+calcd for C 11 H 10 N 2 Na:193.0742,found:193.0735.
Example 46
Preparation of Compound II-46
The procedure is as in example 1, except that compound II-46Prepared by taking alkene I-46 as a substrate.
The yield of the product was 65%, the enantiomeric excess was 84% (determined by chiral HPLCThe method comprises the steps of carrying out a first treatment on the surface of the HPLC analysis was performed using a chiral AZ-H column with isopropyl alcohol to n-hexane 90:10, v:v), 0.8mL/min,220nm,25℃and retention time t R (minor)＝13.43min,t R (major)＝15.88min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.74(dd,J＝8.8,5.6Hz,1H),7.45(dd,J＝8.8,2.4Hz,1H),7.21-7.17(m,1H),4.33(q,J＝7.2Hz,1H),1.73(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)165.34(d,J＝257.5Hz),143.96(d,J＝8.6Hz),135.86(d,J＝9.6Hz),119.39,116.60(d,J＝22.3Hz),115.79,115.55,107.27(d,J＝3.7Hz),30.21,20.99. 19 F NMR(376MHz,Chloroform-d)δ(ppm)-99.59.HRMS(ESI):m/z[M+Na]+calcd for C 10 H 7 FN 2 Na:197.0491,found:197.0481.
Example 47
Preparation of Compound I-47
CuTc (0.0048 mmol,2 mol%) and ligand (0.0048 mmol,2.4 mol%) were dissolved in 4mL of strictly dehydrated DMA at room temperature and stirred for 1 hour under argon. Subsequently Ph-PTZ (0.02 mmol,10 mol%), TMSCN (0.3 mmol,1.5 equiv.) and heavy water (4.0 mmol,1.0 equiv.) are added, the reaction mixture is reacted under 20W violet light until the TLC detection reaction is complete, then 50ml water is added for dilution, extraction four times with 20ml ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and column chromatography is carried out with V petroleum ether/V ethyl acetate=40:1-20:1 to directly give the target product of formula II-1.
Compound II-47Prepared from alkene I-1 AS substrate with 85% yield, 95% deuteration, 90% enantiomeric excess (measured by chiral HPLC; HPLC analysis using chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v: v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝13.18min,t R (major)＝15.79min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.61–7.56(m,4H),7.46–7.34(m,5H),3.93(t,J＝7.4Hz,1H),1.66(d,J＝7.2Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)141.02,140.19,135.92,128.82,127.79,127.56,127.11,127.04,121.54,30.82,21.40–20.93(m).HRMS(ESI):m/z[M+Na]+calcd for C 15 H 12 DNNa:231.1009,found:231.0996.
Example 48
Preparation of Compound I-48
The preparation procedure is as in example I-48, except that compound II-48Is prepared by taking alkene I-2 as a substrate.
The yield of the product was 60%, deuteration 93%, enantiomeric excess 91% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.87min,t R (major)＝12.36min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.62–7.57(m,2H),7.49–7.38(m,4H),7.25(s,2H),3.93(t,J＝7.2Hz,1H),2.40(s,3H),1.66(d,J＝7.2Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)140.96,137.43,137.31,135.61,129.56,127.59,127.08,126.88,121.59,30.83,21.36–20.96(m).HRMS(ESI):m/z[M+Na]+calcd for C 16 H 14 DNNa:245.1165,found:245.1147.
Example 49
Preparation of Compound I-49
The preparation procedure is as in example I-49, except that compound II-49Is prepared by taking alkene I-3 as a substrate.
The yield of the product was 55%, deuteration rate 91%, enantiomeric excess 91% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝11.57min,t R (major)＝10.10min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.60–7.58(m,2H),7.53–7.46(m,4H),7.41–7.39(m,2H),3.92(t,J＝7.2Hz,1H),1.68–1.65(m,2H),1.36(s,9H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)150.65,140.90,137.31,135.62,127.64,127.07,126.69,125.79,121.56,34.53,31.31,30.84,21.31–20.91(m).HRMS(ESI):m/z[M+Na]+calcd for C 19 H 20 DNNa:287.1635,found:287.1625.
Example 50
Preparation of Compound I-50
The preparation procedure is as in example I-50, except that compound II-50Prepared by taking alkene I-4 as a substrate.
The yield of the product was 73%, deuteration 91%, enantiomeric excess 85% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝36.52min,t R (major)＝39.74min. 1 H NMR(400MHz,Chloroform-d)δppm7.58–7.56(m,4H),7.43–7.41(m,2H),7.18–7.16(m,2H),3.94(q,J＝7.6Hz,1H),2.33(s,3H),1.67(d,J＝7.6Hz,3H). 13 C NMR(100MHz,Chloroform-d)δppm 169.53,150.26,140.17,137.97,136.07,128.10,127.76,127.17,121.96,121.48,30.88,21.37,21.12.HRMS(ESI):m/z[M+Na]+calcd for C17H14DNO2:289.1064,found:289.1056.
Example 51
Preparation of Compound I-51
The procedure is as in example I-51, except that compound II-51Prepared by taking alkene I-5 as a substrate.
The yield of the product was 65%, deuteration 95%, enantiomeric excess 90% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝18.80min,t R (major)＝22.16min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.56–7.41(m,6H),7.15–7.10(m,2H),3.94(t,J＝7.2Hz,1H),1.69–1.65(m,2H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)162.56(d,J＝245.4Hz),140.04,136.31(d,J＝3.2Hz),135.96,128.62(d,J＝8.1Hz),127.66,127.18,121.49,115.72(d,J＝21.3Hz),30.81,21.33–20.93(m). 19 F NMR(376MHz,Chloroform-d)δ(ppm)-115.11.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 11 DFNNa:249.0915,found:249.0905.
Example 52
Preparation of Compound I-52
The preparation procedure is as in example I-52, except for II-52Is prepared by taking alkene I-6 as a substrate.
The yield of the product was 53%, deuteration 93%, enantiomeric excess 90% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝15.13min,t R (major)＝16.45min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.72–7.61(m,6H),7.48–7.46(m,2H),3.97(t,J＝7.2Hz,1H),1.68(d,J＝7.2Hz,2H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)143.71,139.59,136.99,129.62(q,J＝32.7Hz),128.00,127.38,127.36,125.80(q,J＝3.7Hz),124.17(q,J＝271.9Hz),121.36,30.89,21.34–20.94(m). 19 F NMR(376MHz,Chloroform-d)δ(ppm)-62.42.HRMS(ESI):m/z[M+Na]+calcd for C 16 H 11 DF 3 N:299.0883,found:299.0845.
Example 53
Preparation of Compound I-53
The preparation procedure is as in example I-53, except that II-53Prepared by taking alkene I-7 as a substrate.
The yield of the product was 67%, deuteration 90%, enantiomeric excess 86% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.90min,t R (major)＝11.45min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.92–7.84(m,2H),7.54–7.38(m,8H),3.98(t,J＝7.2Hz,1H),1.71(d,J＝7.6Hz,2H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)140.70,139.32,136.03,133.84,131.50,130.85,128.42,128.00,127.02,126.75,126.27,125.95,125.80,125.43,121.71,31.05,21.43–21.03(m).HRMS(ESI):m/z[M+Na]+calcd for C 19 H 14 DN:281.1165,found:281.1149.
Example 54
Preparation of Compound I-54
The preparation procedure is as in example I-54, except for II-54Is prepared by taking alkene I-8 as a substrate.
The yield of the product was 68%, deuteration 92%, enantiomeric excess 92% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝16.67min,t R (major)＝20.76min. 1 H NMR(400MHz,Chloroform-d)δppm7.54–7.52(m,3H),7.35–7.30(m,3H),7.21–7.20(m,1H),3.91(t,J＝7.4Hz,1H),1.65–1.63(m,2H). 13 C NMR(100MHz,Chloroform-d)δppm 143.27,135.98,134.21,128.09,127.22,126.49,125.20,123.45,121.41,30.79,21.25–20.85(m).HRMS(ESI):m/z[M+Na]+calcd for C 13 H 10 DNSNa:237.0573,found:237.0575.
Example 55
Preparation of Compound I-55
The preparation procedure is as in example I-55, except for II-55Is prepared by taking alkene I-12 as a substrate.
The yield of the product was 71%, deuteration was 93%, enantiomeric excess was 95%, (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.26min,t R (major)＝9.94min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.57–7.51(m,3H),7.47–7.37(m,4H),7.33–7.30(m,1H),4.21(t,J＝7.2Hz,1H),1.65(d,J＝7.2Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)159.87(d,J＝248.3Hz),143.51(d,J＝7.9Hz),139.02(d,J＝2.0Hz),128.95,128.53(d,J＝3.9Hz),128.14,126.95,123.34(d,J＝3.2Hz),122.87(d,J＝14.5Hz),120.69,114.35(d,J＝21.9Hz),25.09(d,J＝3.4Hz),20.22–19.53(m). 19 F NMR(376MHz,Chloroform-d)δ(ppm)-118.56.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 11 DFNNa:249.0915,found:249.0912.
Example 56
Preparation of Compound I-56
The preparation procedure is as in example I-56, except for II-56Prepared by taking alkene I-15 as a substrate.
The yield of the product was 72%, deuteration 95%, enantiomeric excess 89% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝13.30min,t R (major)＝17.47min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.55–7.36(m,6H),7.23–7.16(m,2H),3.92(t,J＝7.2Hz,1H),1.66(d,J＝7.2Hz,2H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)159.72(d,J＝251.2Hz),138.05(d,J＝7.7Hz),134.87,131.43(d,J＝4.0Hz),128.87(d,J＝3.0Hz),128.50,127.94,122.66(d,J＝3.5Hz),120.97,114.63(d,J＝24.4Hz),30.60(d,J＝1.6Hz),21.06–20.66(m). 19 F NMR(376MHz,Chloroform-d)δ(ppm)-116.30.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 11 DFNNa:249.0915,found:249.0910.
Example 57
Preparation of Compound I-57
The preparation procedure is as in example I-57, except that compound II-57Prepared by taking alkene I-18 as a substrate.
The yield of the product was 48%, deuteration 97%, enantiomeric excess 92% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝29.70min,t R (major)＝13.72min. 1 H NMR(400MHz,Chloroform-d)δppm7.94–7.83(m,3H),7.72–7.66(m,1H),7.60–7.47(m,3H),4.61(t,J＝7.2Hz,1H),1.76(d,J＝6.4Hz,2H). 13 C NMR(100MHz,Chloroform-d)δppm 133.95,132.59,129.75,129.28,128.91,126.89,126.09,125.53,124.66,122.03,121.79,28.14,20.54–20.07(m).HRMS(ESI):m/z[M+Na]+calcd for C 13 H 10 DNNa:205.0852,found:205.0843.
Example 58
Preparation of Compound I-58
The preparation procedure is as in example I-58, except for II-58Prepared by taking alkene I-22 as a substrate.
The yield of the product was 75%, deuteration 99%, enantiomeric excess 87% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝28.76min,t R (major)＝20.03min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.38–7.24(m,8H),7.14–7.12(m,2H),3.99(d,J＝7.6Hz,1H),3.14(dd,J＝21.6,7.2Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ(ppm)136.27,135.23,129.27,129.08,128.68,128.27,127.54,127.45,120.46,42.19–41.50(m),39.79.HRMS(ESI):m/z[M+Na]+calcd for C 15 H 12 DNNa:231.1009,found:231.1000.
Example 59
Preparation of Compound I-59
The preparation procedure is as in example I-59, except for II-59Prepared by taking alkene I-34 as a substrate.
The yield of the product was 65%, deuteration 91%, enantiomeric excess 90% (determined by chiral HPLC; HPLC analysis using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝10.26min,t R (major)＝18.84min. 1 H NMR(400MHz,Acetone-d 6 )δ(ppm)7.44–7.35(m,4H),4.18(t,J＝7.2Hz,1H),1.57(d,J＝7.2Hz,2H),1.49(tt,J＝8.3,5.0Hz,1H),0.92–0.87(m,2H),0.74–0.70(m,2H). 13 C NMR(100MHz,Acetone-d 6 )δ(ppm)138.30,132.94,127.85,124.61,122.31,94.93,75.74,31.22,21.43–21.03(m),8.97,0.58.HRMS(ESI):m/z[M+H]+calcd for C 14 H 13 DN:197.1189,found:197.1179.
Example 60
Preparation of Compound I-60
The preparation procedure is as in example I-60, except that compound II-60Is prepared by taking alkene I-35 as a substrate.
The yield of the product was 56%, deuteration 93%, enantiomeric excess 92% (determined by chiral HPLC; HPLC analysis using a chiral OD-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.95min,t R (major)＝11.20min. 1 H NMR(400MHz,Acetone-d 6 )δ(ppm)7.48–7.41(m,4H),4.20(t,J＝7.2Hz,1H),3.79(t,J＝6.4Hz,2H),2.62(t,J＝7.0Hz,2H),2.06(p,J＝6.6,Hz,2H),1.59(d,J＝7.2Hz,2H). 13 C NMR(100MHz,Acetone-d 6 )δ(ppm)138.65,133.01,127.91,124.30,122.28,89.82,81.46,44.62,32.35,31.25,21.44–21.04(m),17.20.HRMS(ESI):m/z[M+H]+calcd for C 14 H 14 DClN:233.0956,found:233.0950.
Example 61
Preparation of Compound I-61
The preparation procedure is as in example I-61, except that compound II-61Prepared by taking alkene I-37 as a substrate.
The yield of the product was 64%, deuteration was 87%, enantiomeric excess was 92% (determined by chiral HPLC; HPLC analysis was performed using a chiral OD-H column with isopropyl alcohol: n-hexane 95:5, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝22.13min,t R (major)＝20.71min. 1 H NMR(400MHz,Acetone-d 6 )δ(ppm)7.77–7.76(m,1H),7.59–7.48(m,5H),7.26–7.24(m,1H),4.24(t,J＝7.2Hz,1H),1.62(d,J＝7.2Hz,1H). 13 C NMR(100MHz,Acetone-d 6 )δ(ppm)139.23,132.91,130.61,130.25,128.13,127.18,123.74,122.84,122.25,88.79,85.93,31.32,21.42–21.02(m).HRMS(ESI):m/z[M+Na]+calcd for C 15 H 10 DNSNa:261.0573,found:261.0570.
Example 62
Preparation of Compound I-62
The procedure is as in example I-62, except that compound II-62Prepared by taking alkene I-39 as a substrate.
The yield of the product was 60%, deuteration 93%, enantiomeric excess 94% (determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column with isopropyl alcohol: n-hexane 90:10, v:v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝18.72min,t R (major)＝14.95min. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.74–7.68(m,3H),7.50–7.46(m,1H),4.33(t,J＝7.2Hz,1H),1.71(d,J＝6.0Hz,2H). 13 CNMR(100MHz,Chloroform-d)δ(ppm)140.64,133.87,133.39,128.77,127.62,120.00,116.52,111.15,30.10,21.17–20.77(m).HRMS(ESI):m/z[M+Na]+calcd for C 10 H 7 DN 2 Na:180.0648,found:180.0644.
Example 63
Synthesis of flurbiprofen axetil:
compound II-15 (0.2 mmol) was dissolved in 4mL of methanol at room temperature, then 2mL of 37% HCl was slowly added dropwise, the reaction mixture was reacted at 80℃until the TLC was complete, then the solvent was removed by evaporation in vacuo, 10mL of water was added, extraction was performed three times with 10mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and flurbiprofen axetil was directly obtained by column chromatography with V Petroleum ether/V ethyl acetate=40:1-20:1.
The yield of the product was 72%, the enantiomeric excess was 89% (determined by chiral HPLC; HPLC analysis using a chiral OX-H column with isopropyl alcohol: n-hexane 95:5, v: v), 0.8mL/min,254nm,25℃and retention time t R (minor)＝9.89min,t R (major)＝10.44min. 1 H NMR(400MHz,Chloroform-d)δ((ppm))7.54–7.51(m,2H),7.45–7.33(m,4H),7.15–7.10(m,2H),3.76(q,J＝7.2Hz,1H),3.70(s,3H),1.53(d,J＝7.2Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ((ppm))174.42,159.67(d,J＝246.8Hz),141.78(d,J＝7.5Hz),135.48,130.80(d,J＝4.0Hz),128.92(d,J＝2.9Hz),128.42,127.83(d,J＝13.6Hz),127.64,123.49(d,J＝3.4Hz),115.21(d,J＝23.5Hz),52.19,44.89(d,J＝1.5Hz),18.41. 19 F NMR(376MHz,Chloroform-d)δ((ppm))-117.58.HRMS(ESI):m/z[M+Na]+calcd for C 16 H1 5 FO 2 :281.0954,found:281.0948.
Comparative example 1
The preparation was the same as in example 1, except that no copper catalyst was added, and no product II-1 was obtained.
Comparative example 2
The preparation was identical to example 1, except that no photocatalyst Ph-PTZ was added and the substrate was unreacted.
Based on the method of the invention, the invention combines visible light catalysis and copper catalysis, uses water as a hydrogen source, uses olefin compounds as raw materials, uses TMSCN as a nitrile source and uses heavy water as a deuterium source to prepare the corresponding deuterium-substituted chiral nitrile compound.
Examples 64 to 70
The preparation process was the same as in example 1, except that the copper catalyst was different, and the specific copper catalyst is shown in table 1.
Table 1. Product yields and enantiomeric excess values for examples 64-70.
Examples Copper catalyst Yield (%) Enantiomeric excess (%)
Example 1 CuTc 93 92
Example 64 [Cu(MeCN) 4 ]PF 6 93 91
Example 65 CuBr 83 92
Example 66 CuCl 76 92
Example 67 Cu(OAc) 88 90
Example 68 CuSCN 85 88
Example 69 Cu(OTf) 90 87
Example 70 Cu(OTf) 2 95 88
Examples 71 to 72
The preparation process was the same as in example 1, except that the organic solvents were different, see table 1 for specific organic solvents.
Table 2. Product yields and enantiomeric excess values for examples 71-72.
Examples Organic solvents Yield (%) Enantiomeric excess (%)
Example 1 DMA 93 92
Example 71 MeCN 88 71
Example 72 MeOH 18 80
As can be seen from table 1, when the organic solvent was DMA, the yield of the product was higher and the selectivity was higher.
Examples 73 to 74
The preparation was carried out as in example 1, except that the chiral oxazoline ligands were different, and the structures of the specific chiral oxazoline ligands are shown in Table 3.
Table 3. Product yields and enantiomeric excess values for examples 73-77.
Examples Ligand Yield (%) Enantiomeric excess (%)
Example 1 L1 93 92
Example 73 L2 73 81
Example 74 L3 84 -83
Example 75 L4 36 25
Example 76 L5 69 -67
Example 77 L6 63 57
As can be seen from Table 3, the yield and selectivity of the structure of formula II-1 are much higher for the ligands L1, L2, and especially for L1 than for the other ligands.
Although embodiments of the present invention have been described in detail above, one of ordinary skill in the art will appreciate that: many changes, modifications, substitutions and variations may be made to the embodiments without departing from the spirit and principles of the invention, the scope of which is defined by the claims and their equivalents.

Claims (7)

1. The synthesis method of the chiral nitrile compound is characterized by comprising the following steps: under the protection of inert gas, in an organic solvent, in the presence of a photocatalyst Ph-PTZ, a copper catalyst, a chiral oxazoline ligand, TMSCN, water and ultraviolet irradiation, converting the olefin compound into a chiral nitrile compound, wherein the reaction is shown as the following formula, the olefin compound is shown as the formula I-a, the formula I-b or the formula I-c, and the chiral nitrile compound is shown as the formula II-a, the formula II-b or the formula II-c:
in each reaction formula, ring a is aryl or heteroaryl;
the R is 1 、R 2 、R 3 The structure of (2) is selected as follows:
R 2 or R is 3 One of which is H and the other is cyano, ester or alkenyl, said R 1 Is a single substituent or multiple substituents, and each substituent in the single substituent and the multiple substituents is independently selected from one of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted double bond, substituted or unsubstituted triple bond and cyano;
alternatively, the R 2 Or R is 3 One of them is H and the other is alkyl, or R 2 And R is R 3 A cyclic, ring system 3 membered carbocyclic ring, said R 1 Is a single substituent or multiple substituents, and each substituent in the single substituent and the multiple substituents is independently selected from one of substituted or unsubstituted aryl, substituted or unsubstituted double bond, substituted or unsubstituted triple bond, or cyano;
alternatively, R 2 Is H, said R 1 And R is R 3 Forming a ring, wherein the ring system is a 6-membered alicyclic ring;
the R is 4 、R 5 The structure of (2) is selected as follows:
R 4 one selected from halogen, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted triple bond and cyano, and two R in the same structure 4 The substitution sites on ring A are the same;
R 5 one selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted double bond, a substituted or unsubstituted triple bond, or a cyano group;
the organic solvent is selected from one or more of N, N-dimethylacetamide, acetonitrile or methanol;
the copper catalyst is selected from [ Cu (MeCN) 4 ]PF 6 CuTc, cuBr, cuCl, cu (OAc), cuSCN, cu (OTf) or Cu (OTf) 2 One or more of the following;
the chiral oxazoline ligand is selected from one or more of the following structures:
2. the method for synthesizing chiral nitrile compound according to claim 1, wherein the chiral oxazoline ligand is one selected from the group consisting of L1, L2 and L6.
3. The method for synthesizing chiral nitrile compound according to claim 1, wherein said organic solvent is N, N-dimethylacetamide.
4. The method for synthesizing chiral nitrile compound according to claim 1, wherein the ratio of the amounts of the copper catalyst, chiral oxazoline ligand, photocatalyst Ph-PTZ, trimethylcyanosilane TMSCN, olefinic compound and water is (1% -3%): (2% -4%): (8% -12%): (1-2): (0.5-1.5): (0.5-1.5).
5. The method for synthesizing chiral nitrile compound according to claim 1, wherein in the process of converting the olefin compound into the chiral nitrile compound, the progress of the reaction is monitored by TLC, after the reaction is completed, diluted reaction solution is added, extracted with ethyl acetate, and the organic phase is dried with anhydrous sulfuric acid and then subjected to column chromatography to obtain the chiral nitrile compound.
6. The method for synthesizing chiral nitrile compound according to claim 5, wherein the column chromatography adopts a silica gel column, and petroleum ether-ethyl acetate with a volume ratio of 40:1 to 20:1 is used as an eluent for gradient elution, so as to obtain the chiral nitrile compound.
7. The method for synthesizing chiral nitrile compound according to claim 1, wherein said olefinic compound is selected from one of the following structures:
the chiral nitrile compound is selected from one of the following structures:
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