CN102432526A

CN102432526A - Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof

Info

Publication number: CN102432526A
Application number: CN2011102625742A
Authority: CN
Inventors: 王兴旺; 贾俊; 赵华; 蓝玉胞
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2011-09-06
Filing date: 2011-09-06
Publication date: 2012-05-02

Abstract

The invention belongs to the field of asymmetric catalysis, and specifically relates to a method for synthesizing a novel chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile compound. According to the invention, chiral primary amine derived from quinine is adopted as a catalyst, and chiral or achiral Brownst acid is adopted as a co-catalyst, such that the compound is synthesized under catalyzing. According to the invention, the chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile compound is synthesized through a dual-Michael addition reaction of an isatin malononitrile condensation substance and methyl aryl alpha,beta-unsaturated ketone. The synthesizing method is advantaged in simple raw materials which are easy to acquire, convenient operation, and good substrate compatibility. A plurality of chiral centers can be established with a one-kettle method. Under a high-temperature reaction condition, high yield and high conversion frequency are realized, and excellent enantioselectivity and excellent diastereoselectivity can be realized.

Description

Chirality 2', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3'-indoles]-2,2-two carbonitrile derivatives and preparation thereof

Technical field

The invention belongs to asymmetric catalysis field, be specifically related to a kind of with chiral primary amine catalyzer and protonic acid altogether catalytic preparation chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the method for 2-two nitrile compounds.

Background technology

The volution oxindole structural unit of chirality extensively is present in natural product and the biologically active drug molecule.Because this compounds has stronger biological activity and higher structural complexity-stereoselective structure quaternary carbon center, therefore efficient synthetic this compounds is a focus of organic synthesis research, and has caused the very big interest of Synthetic Organic Chemistry man.

Through designing dissimilar reaction substrates and chiral ligand, the volution oxindole of multiclass chirality is synthesized in the catalytic asymmetric reaction of applied metal, as: asymmetric Heck reaction, asymmetric allyl substitution reaction, asymmetric 3+2 cycloaddition reaction etc.

Along with the catalytic further investigation of organic molecule; Catalytic cascade reaction of organic molecule or domino reaction become the compound method of synthesis of cyclic compound; And be applied to the chipal compounds of synthetic polysubstituted volution oxindole skeleton efficiently, and as: volution [oxindole-Pyrrolidine] verivate, volution [oxindole-tetrahydropyrans] verivate, volution [oxindole-hexamethylene olefine aldehydr] verivate, volution [oxindole-cyclohexenol] verivate etc.

Because containing the compound of volution [oxindole-cyclonene] skeleton is one type of important phenylalkylamine alkaloid compounds; Have potential physiologically active and pharmacologically active, medicament research and development company and Synthetic Organic Chemistry man have had further research in this respect recently:

(1) about the research of pharmaceutical activity, Pharmaceutical Chemist finds that the multiple volution oxindole compound that contains has physiology and pharmacologically active widely, and for example: Chitosenine has the effect of the neural transmission of of short duration inhibition in organism; NITD609 has and kills the plasmodium that causes malaria in the blood; Strychnofoline can suppress indirect nuclear division in the various kinds of cell body; Kounidine (Gelsemine) is a plant elegant jessamine extract, though the people is had severe toxicity, has the effect that improves breeding performonce fo animals, therefore can replace country to ban use of the microbiotic in animal grain; Compd A not only has contraceptive efficacy with the gynopathic drug candidate of a kind of treatment, and can treat the relevant canceration of fibroma uteri, endometriosis and hormone; B is a kind of non-effectively peptide MDM2 suppressor factor, has effect (reference: S.Sakai, N.Aimi, K.Yamaguchi, H.Ohhira, K.Hori and J.Haginiwa, Tetrahedron Lett., 1975,16,715 of antiproliferative, anticancer cell; S.Sakai, N.Aimi, K.Yamaguchi, E.Yamanaka and J.Haginiwa, J.Chem.Soc.Perkin Trans 1., 1982,1257; M.Rottmann, et al.Science., 2010,329,1175; B.Tan, N.R.Candeias and C.F Barbas III, Nat.Chem., 2011,3,473; O.Dideberg, J.Lamotte-Brasseur, L. Dupont, H.Campsteyn, M.Vermeire, L.Angenot, Acta Crystallogr.Sect.B., 1977,33,1796; A.Fensome, R.Bender, J.Cohen, M.A.Collins, V.A.Mackner, L.L.Miller, J.W.Ullrich, R.Winneker, J.Wrobel, P.Zhang, Z.Zhang, Y.Zhu, Bioorg.Med.Chem.Lett.2002,12,3487-3490; A.Fensome, W.R.Adams, A.L.Adams, T.J.Berrodin, J.Cohen, C.Huselton; A.Illenberger, J.C.Kern, V.A.Hudak, M.A.Marella, E.G.Melenski, C.C.McComas; C.A.Mugford, O.D.Slayden, M.Yudt, Z.Zhang, P.Zhang, Y.Zhu; R.C.Winneker, J.E.Wrobel, J.Med.Chem.2008,51,1861-1873; Q.Ding, J.-J.Liu, Z.Zhang, WO 2007/104714,2007).

(2) 2008 years Roche drugmakers disclose the biological medicine of a kind of volution [oxindole-cyclonene] skeleton, PCT international application no WO2008/055812.Announced also that simultaneously this compound is used as and application (reference: Liu, the J.-J. of the interactional anti-antagonistic agent of MDM2 with the preparation antitumor and anticancer agent; Zhang, Z; (Hoffmann-LaRoche AG), PCT Int.Appl.WO2008/055812,2008), its structural formula is as follows:

(3) external Melchiorre seminar is catalyst 3-benzylidenei indol-2-one (3-benzylideneindolin-2-one with Chiral Amine and o-fluorobenzoic acid; CAS number: 3359-49-7) with alpha, beta-unsaturated ketone reaction synthesis of chiral volution [hexanaphthene-1,3 '-indoles]-2; 4 '-diketone [s piro [cyclohexane-1; 3 '-indoline]-2 ', 4-diones] and compounds (referring to: Bencivenni, G.; Wu, L.Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F; Song, M.P.; Bartoli, G.; Melchiorre, P.Angew.Chem.Int.Ed.2009,48,7200), the total formula of its structure is as follows:

(4) Gong Liuzhu group finds with the bronsted acid of cyclohexanediamine deutero--Lewis base bifunctional catalysis agent catalysis 3-benzylidenei indol-2-one and α; β-unsaturated 1, and the cascade reaction of 3-dicarbonyl compound (Nazarov reagent) can obtain chiral spiro [hexanaphthene-1 by highly-solid selectively; 3 '-indoles]-2 '; The 4-diketone [spiro [cyclohexane-1,3 '-indoline]-2 ', 4-diones] compounds; And successfully synthesize the chirality anti-tumor agent comprising salmosin (referring to Q.Wei, L.-Z.Gong, Org.Lett.2010,12,1008.) of Roche drugmaker research and development with this method.

(5) Wang Lixin seminar has reported that quinine deutero-primary amine and bronsted acid are catalyzer recently, two Michael reactions of the oxindole compounds of catalyzing N-protection and diketene, the generation chiral spiro [hexanaphthene-1,3 '-indoles]-2 '; The 4-diketone [spiro [cyclohexane-1,3 '-indoline]-2 ', 4-diones] and compounds (referring to: L.-L.Wang; L.Peng, J.-F.Bai, L.-N.Jia; X.-Y.Luo, Q.C.Huang, L.-X.Wang; Chem.Commum.2011,47,5593.).

Although the synthesizing spiro oxindole compounds of having reported has a lot; But find through consulting document; So far do not have bibliographical information chiral spiro [hexanaphthene-1,3 '-indoles]-2 ', 3-diketone [s piro [cyclohexane-1; 3 '-indoline]-2 ', 3-diones] framework compound synthetic.

Summary of the invention

Goal of the invention of the present invention provide a kind of chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives and preparation method thereof.

For reaching the foregoing invention purpose, the technical scheme that the present invention adopts is: a kind of chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives, its chemical structural formula is:

In the formula, the R substituting group is selected from: a kind of in hydrogen, halogen, methyl, methoxyl group or the trifluoromethoxy; Aryl Ar is selected from: phenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, p-methylphenyl, p-isopropyl phenyl, p-trifluoromethyl phenyl, adjacent fluorophenyl, Chloro-O-Phenyl, o-methoxyphenyl, 2, a kind of in 4-dimethoxy phenyl, a chloro-phenyl-, 1-naphthyl, 2-furans or the 2-thienyl.

Preferably, in the technique scheme, when chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the chemical structural formula of 2-two carbonitrile derivatives is:

When

, the R substituting group is selected from: a kind of in hydrogen, 4-chlorine, 4-bromine, 5-methyl, 5-bromine, 5-chlorine, 5-fluorine, 5-methoxyl group, 6-bromine or the 7-trifluoromethyl;

When chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the chemical structural formula of 2-two carbonitrile derivatives is:

When

, R is a fluorine.

The present invention provide simultaneously above-mentioned chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2; The preparation method of 2-two carbonitrile derivatives: with isatin propane dinitrile condenses and methyl aryl α, beta-unsaturated carbonyl compound is a reaction substrate, in the presence of catalyzer and additive; Through two Michael reactions, prepare chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1; 3 '-indoles]-2,2-two carbonitrile derivatives;

Wherein, said isatin propane dinitrile condenses is selected from:

Said methyl aryl α, the chemical structural formula of beta-unsaturated carbonyl compound is:

Said catalyzer is selected from:

; (catalyst I) or

; (catalyst I I);

Said additive is selected from: phenylformic acid

CO ₂H, p-Nitrobenzenecarboxylic acid O ₂N

CO ₂H, trifluoroacetic acid CF ₃CO ₂H, Boc-L-phenylglycine The Boc-D-phenylglycine

R-BINOL phosphoric acid Or S-BINOL phosphoric acid

In a kind of.

In the technique scheme, said preparation process is carried out in solution, and said solvent is selected from: methylene dichloride, 1, a kind of in 2-ethylene dichloride, chloroform, THF, acetonitrile, the toluene; Preferably, said solvent is selected from: 1, and 2-ethylene dichloride or toluene.

In the technique scheme, isatin propane dinitrile condenses and methyl aryl α, the mol ratio of beta-unsaturated carbonyl compound is 1: 2.

In the technique scheme, said catalyst consumption is the 5-20% of isatin propane dinitrile condenses amount of substance, and the consumption of additive is the 10-40% of isatin propane dinitrile condenses amount of substance.

In the technique scheme; The Knoevenagel condensation reaction takes place by Isatine derivatives and propane dinitrile and makes in said isatin propane dinitrile condenses; Wherein, Isatine derivatives comprises: isatin, 4-chlorisatide, 4-bromo-isatin, 5-methyl isatin, 5-bromoisatin, 5-chlorisatide, 5-fluoro indigo red, 5, a kind of in 6-two fluoro indigo reds, 5-methoxyl group isatin, 6-bromo-isatin, the 7-trifluoromethyl isatin.

In the technique scheme, said methyl aryl α, beta-unsaturated carbonyl compound is obtained by aromatic aldehyde and condensation of acetone.

Particularly, above-mentioned chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1; 3 '-indoles]-2, the preparation method of 2-two carbonitrile derivatives is: with 1,2-ethylene dichloride or toluene are solvent; With isatin propane dinitrile condenses and methyl aryl α, beta-unsaturated carbonyl compound is a reaction substrate, in the presence of catalyzer and additive; Through two Michael reactions, in 25～110 ℃ of down reactions more than 1.0 hours, make 2 '; 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives.

In the optimized technical scheme, when with 1, when the 2-ethylene dichloride is solvent; When 4 bit substituents in the substrate isatin propane dinitrile verivate were chlorine or bromine, temperature of reaction was 40 ℃, and the reaction times extends to 36 hours; Other substrate reactions temperature is 80 ℃, and the reaction times is 1.5～4.7 hours.When being solvent with toluene, when temperature of reaction was 100 ℃ or 110 ℃, the reaction times was 1.0～2.5 hours.

Further in the technical scheme; After reaction finished, system was used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Decompression is steamed down and is desolventized, and (eluent is an ETHYLE ACETATE to crude product: sherwood oil=1: 2～1: 4) can obtain title product through simple column chromatography.

Because the technique scheme utilization, the present invention compared with prior art has advantage:

1. the present invention has realized that first with quinine deutero-chirality quinine amine be that catalyzer and R-BINOL phosphoric acid are under the additive condition; Catalysis isatin propane dinitrile condenses and α; Two Michael reactions of alpha, beta-unsaturated ketone, the chirality 2 of synthesizing new ', 5-dioxy-3-aryl base spiral shell [hexanaphthene-1; 3 '-indoles]-2,2-two nitrile compounds.

2. preparing method's raw material according to the invention is simple and easy to; Easy and simple to handle; The substrate compatibility is good, can make up a plurality of chiral centres by one kettle way, is reflected at and has not only realized high yield under the hot conditions; High transformation frequency (TOF), and can realize outstanding cis-selectivity and outstanding enantioselectivity.

Embodiment

Below in conjunction with embodiment the present invention is further described:

Material:

Catalyzer:

Additive:

Above-mentioned catalyzer and additive belong to prior art, and (preparation of catalyst I and II can be referring to document: L.M.-A.Rogers, J.Rouden, L.Lecomte, M.-C.Lasne, Tetrahedron Lett.2003,44,3047-3050; W.He:P.Liu; B.L.Zhang, X.L.Sun, S.Y.Zhang, Applied Organometallic Chemistry 2006,20,328-334; R.P.Singh, K.Bartelson, Y.Wang, H.Su, X.Lu, L.Deng, J.Am.Chem.Soc.2008,130,2422-2423. additive merchandise news: phenylformic acid A1, CAS number: 65-85-0; P-Nitrobenzenecarboxylic acid A2, CAS number: 62-23-7; Trifluoroacetic acid A3, CAS number: 76-05-1; Boc-L-phenylglycine A4, CAS number: 2900-27-8; Boc-D-phenylglycine A5, CAS number: 33125-05-2; R-BINOL phosphoric acid A6, CAS number: 39648-67-4; S-BINOL phosphoric acid A7, CAS number: 35193-64-7).

Above-mentioned substrate 1 and 2 preparation method belong to prior art, and (the synthetic of substrate 1a-k can be referring to document: X.Li, L.Li, Y.Tang; L.Zhong, L.Cun, J.Zhu; J.Liao, J.Deng, J.Org.Chem.2010; 75, the synthetic of 2891-2988. substrate 2a-p can be referring to document: S.J.Garden, C.R.W.

M.B.Corre á; C.A.F de Oliveira, A.Da Cunha Pinto, R.B.de Alencastro; J.Org.Chem.2003,68,8815-8822.)

Embodiment one:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 1 (4.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride at room temperature reacted 42 hours, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (29.0mg), yield is 85% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 16:84dr, and 99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: tR=14.059min (inferior) with HPLC; TR=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment two:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 2 (6.7mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 7 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (31.4mg), yield is 92% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 17:83dr, 90%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment three:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 3 (4.6mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride at room temperature reacted 96 hours, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (29.0mg), yield is 85% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 93:7dr, 92%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment four:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 4 (10.0mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds l mL 1 to 1a; The 2-ethylene dichloride reacted 7 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (27.3mg), yield is 80% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 34:66dr, 91%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment five:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 5 (10.0mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 6 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.1mg), yield is 97% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 41:59dr, 94%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=δ .0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment six:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 6 (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 1.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.8mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). [α] _D ²⁵+ 28.1 (c 0.27in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment seven:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 7 (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.8mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). [α] _D ²⁵+ 27.6 (c 0.5in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment eight:

Pack into successively in the reaction flask quinine butylamine II (6.5mg, 0.02mmol), additive A 6 (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 1 hour down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.8mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 93:7dr ,-86%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment nine:

Pack into successively in the reaction flask quinine butylamine II (6.5mg, 0.02mmol), additive A 7 (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 30 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.8mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 85:15dr ,-90%ee. measures [Dai celChiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.059min (inferior); t _R=14.973min (master). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment ten:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (22.9mg 0.1mmol), adds 1mL 1 to 1b; The 2-ethylene dichloride reacted 36 hours down at 40 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3b (33.75mg), yield is 90% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr, 98.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=27.256min (inferior); t _R=28.653min (master). [α] _D ²⁵-15.2 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.56 (s, 1H), 7.47-7.43 (m, 6H), 7.21 (d, J=8.0Hz, 1H); 7.03 (d, J=8.0Hz, 1H), 4.43 (dd, J=16.0,4.0Hz, 1H); 3.43 (t, J=16.0Hz, 1H), 3.21 (d, J=20.0Hz, 1H), 2.98 (d; J=16.0Hz, 1H), 2.92 (dd, J=16.0,4.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.27,178.86,150.88,140.41,138.43,136.65,135.14,134.75,134.43,129.76,129.32,118.17,116.73,115.74,65.42,61.11,53.09,51.56,46.47.HRMS:calcd.for C ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0777. product prepares successfully.

Embodiment 11:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (27.3mg 0.1mmol), adds 1mL 1 to 1c; The 2-ethylene dichloride reacted 36 hours down at 40 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3c (36.87mg), yield is 88% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=13.499min (inferior); t _R=14.089min (master). [α] _D ²⁵+ 11.4 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.53 (s, 1H), 7.50-7.44 (m, 5H), 7.38-7.33 (m, 2H), 7.08-7.04 (m, 1H), 4.59 (dd, J=16.0,4.0Hz, 1H), 3.44-3.32 (m, 2H), 2.91 (dd, J=16.0,4.0Hz, 1H), 2.85 (d, J=20.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.51,179.34,150.95,140.39,138.45,135.12,134.74,134.44,133.04,131.42,125.77,118.34,117.29,116.15,84.81,61.21,52.56,51.11,46.26.HRMS:calcd.for C ₂₁H ₁₄BrN ₃O ₂419.0269 the above digital proof purpose of found:419.0243. product prepares successfully.

Embodiment 12:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (22.5mg 0.1mmol), adds 1mL 1 to 1d; The 2-ethylene dichloride reacted 2 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3d (36.73mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=13.926min (master); t _R=18.960min (inferior). [α] _D ²⁵+ 96.8 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.14 (s, 1H), 7.51-7.34 (m, 5H), 7.05-6.95 (m, 3H), 4.31 (dd, J=12.0; 3.0Hz, 1H), 3.75 (s, 3H), 3.55 (t, J=15.0Hz, 1H), 3.24 (d; J=15.0Hz, 1H), 2.86 (d, J=15.0Hz, 1H), 2.46 (d, J=12.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.65,173.32,155.83,136.00,135.37,135.24,129.93,129.23,127.31,115.54,114.62,113.19,112.00,111.77,56.41,54.66,46.40,45.69,43.28,42.20.HRMS:calcd.for C ₂₂H ₁₇N ₃O ₃371.1270 the above digital proof purpose of found:371.1272. product prepares successfully.

Embodiment 13:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (20.9mg 0.1mmol), adds 1mL 1 to 1e; The 2-ethylene dichloride reacted 4.7 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3e (32.66mg), yield is 92% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 98:2dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=9.772min (master); t _R=10.426min (inferior). [α] _D ²⁵+ 98.4 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.24 (s, 1H), 7.47-7.43 (m, 5H), 7.35 (s, 1H), 7.24 (d, J=6.0Hz; 1H), 6.95 (d, J=6.0Hz, 1H), 4.38 (dd, J=12.0,4.0Hz, 1H); 3.59 (t, J=12.0Hz, 1H), 3.27 (d, J=12.0Hz, 1H), 2.86 (dd, J=16.0; 4.0Hz, 1H), 2.48 (d, J=16.0Hz, 1H), 2.33 (s, 3H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.63,173.53,140.37,135.38,132.54,131.91,130.04,129.90,129.28,127.40,126.22,113.23,111.86,111.30,54.34,46.50,45.64,43.29,42.34,21.31.HRMS:calcd.for C ₂₂H ₁₇N ₃O ₂355.1321 the above digital proof purpose of found:355.1320. product prepares successfully.

Embodiment 14:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (21.3mg 0.1mmol), adds 1mL 1 to 1f; The 2-ethylene dichloride reacted 2.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3f (35.54mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=9.754min (inferior); t _R=10.669min (master). [α] _D ²⁵+ 16.9 (c 0.42in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.32 (s, 1H), 7.55-7.52 (m, 1H), 7.49-7.36 (m, 5H), 7.32-7.26 (m; 1H), 7.05-7.01 (m, 1H), 4.33 (dd, J=12.0,3.0Hz, 1H); 3.55 (t, J=15.0Hz, 1H), 3.24 (d, J=15.0Hz, 1H); 2.80 (d, J=15.0Hz, 1H), 2.54 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 203.38,173.48,157.32,139.21,135.30,130.04,129.88,129.28; 127.41,127.33,114.94,114.90,113.04,112.60,112.53,112.43; 112.35,111.59,54.77,46.23,45.66,43.04,42.28.HRMS:calcd.for C ₂₁H ₁₄FN ₃O ₂359.1070 the above digital proof purpose of found:359.1072. product prepares successfully.

Embodiment 15:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (22.9mg 0.1mmol), adds 1mL 1 to 1g; The 2-ethylene dichloride reacted 5.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3g (34.50mg), yield is 92% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=10.291 (inferior); t _R=11.968min (master). [α] _D ²⁵+ 100.8 (c 0.47in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.51 (s, 1H), 7.75-7.61 (m, 1H), 7.54-7.35 (m, 6H), 7.11-7.08 (m, 1H); 4.38 (dd, J=12.0,3.0Hz, 1H), 3.60 (t, J=15.0Hz, 1H), 3.29 (d; J=15.0Hz, 1H), 2.89 (d, J=15.0Hz, 1H), 2.62 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.44,173.31,141.94,135.27,131.72,130.04,129.89,129.27,128.00,127.48,126.84,113.05,112.98,111.56,54.66,46.29,45.69,42.94,42.26.HRMS:calcd.for C ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0778. product prepares successfully.

Embodiment 16:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (27.3mg 0.1mmol), adds 1mL 1 to 1h; The 2-ethylene dichloride reacted 3.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3h (39.80mg), yield is 95% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=10.840 (inferior); t _R=12.589min (master). [α] _D ²⁵+ 120.0 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.44 (s, 1H), 7.78-7.67 (m, 1H), 7.63-7.60 (m, 1H), 7.51-7.35 (m; 5H), 7.00-6.97 (m, 1H), 4.32 (dd, J=12.0,3.0Hz, 1H); 3.53 (t, J=12.0Hz, 1H), 3.21 (d, J=15.0Hz, 1H); 2.83 (d, J=15.0Hz, 1H), 2.57 (d, J=18.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 203.46,173.19,142.34,135.29,134.65,134.61,130.03,129.89,129.28,128.42,115.12,113.43,113.07,111.55,54.76,46.32,45.68,42.91,42.25.HRMS:calcd.for C ₂₁H ₁₄BrN ₃O ₂419.0269 the above digital proof purpose of found:419.0273. product prepares successfully.

Embodiment 17:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (27.3mg 0.1mmol), adds 1mL 1 to 1i; The 2-ethylene dichloride reacted 3.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3i (41.48mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 0.3mL/min]: t with HPLC _R=45.981min (master). [α] _D ²⁵+ 62.8 (c 0.67in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.51 (s, 1H), 7.50-7.44 (m, 6H), 7.32-7.29 (m, 1H), 7.26-7.15 (m, 1H); 4.27 (dd, J=15.0,3.0Hz, 1H), 3.59 (t, J=15.0Hz, 1H), 3.26 (d; J=9.0Hz, 1H), 2.81 (d, J=12.0Hz, 1H), 2.57 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.37,173.46,144.62,135.19,130.11,129.82,129.34,128.74,125.81,125.40,124.69,114.43,113.01,111.55,54.20,46.27,45.81,42.90,42.31.HRMS:calcd.for C ₂₁H ₁₄BrN ₃O ₂419.0269 the above digital proof purpose of found:419.0271. product prepares successfully.

Embodiment 18:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (23.1mg 0.1mmol), adds 1mL 1 to 1j; The 2-ethylene dichloride reacted 4.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3j (36.19mg), yield is 96% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 96%yield, and＞99:1dr, 98%ee measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=8.733 (inferior), t _R=10.188min (master). [α] _D ²⁵+ 2.4 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.48 (s, 1H), 7.82-7.77 (m, 1H), 7.52-7.36 (m, 5H), 7.14-7.08 (m, 1H); 4.30 (dd, J=15.0,3.0Hz, 1H), 3.55 (t, J=15.0Hz, 1H), 3.22 (d; J=15.0Hz, 1H), 2.79 (d, J=15.0Hz, 1H), 2.56 (d, J=18.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 203.24,173.98,152.85,150.51,150.38,147.36,144.84,140.18; 140.08,135.23,130.07,129.86,129.29,121.84,117.29,117.05; 112.96,111.48,54.51,46.26,45.59,42.95,42.29.HRMS:calcd.forC ₂₁H ₁₃F ₂N ₃O ₂377.0976 the above digital proof purpose of found:377.0975. product prepares successfully.

Embodiment 19:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (26.3mg 0.1mmol), adds 1mL 1 to 1k; The 2-ethylene dichloride reacted 1.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3k (40.49mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 96:4dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=70: 30, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=12.493 (inferior), t _R=17.925min (master). [α] _D ²⁵-8.9 (c 0.56in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.79 (s, 1H), 7.81-7.73 (m, 2H), 7.56-7.39 (m, 5H), 7.32-7.26 (m, 1H), 4.30 (dd; J=12.0,3.0Hz, 1H), 3.61 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz; 1H), 2.81 (dd, J=15.0,3.0Hz, 1H), 2.69 (d, J=15.0Hz, 1H). ¹³CNMR (100MHz, DMSO-d ₆) δ 203.41,174.20,140.52,135.15,130.92,130.15,129.83,129.35; 128.03,125.22,123.33,123.28,122.51,112.88,112.75; 112.42,111.44,53.44,46.48,45.68,42.58,42.28.HRMS:calcd.for C ₂₂H ₁₄F ₃N ₃O ₂409.1038 the above digital proof purpose of found:409.1037. product prepares successfully.

Embodiment 20:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg; 0.04mmol) and 2b (35.2mg, 0.2mmol), 1a (19.5mg; 0.1mmol), add 1mL 1, the 2-ethylene dichloride; Reacted 1.5 hours down at 80 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3l (33.76mg), yield is 91% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 94:6dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 0.5mL/min]: t with HPLC _R=81.171min (master). [α] _D ²⁵+ 28.3 (c 0.58in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.31 (s, 1H), 7.60-7.57 (m, 1H), 7.46-7.36 (m, 3H), 7.16-7.01 (m; 4H), 5.03 (dd, J=12.0,3.0Hz, 1H), 3.53 (s, 3H); 3.43 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz, 1H); 2.72 (d, J=15.0Hz, 1H), 2.51 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.74,173.66,157.40,143.08,131.63,131.17,128.80,126.65; 126.15,123.62,122.96,121.33,112.91,112.19,111.89; 111.63,56.17,54.36,45.95,43.41,42.13,36.46.HRMS:calcd.for C ₂₂H ₁₇N ₃O ₃371.1270 the above digital proof purpose of found:371.1268. product prepares successfully.

Embodiment 21:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2c (32.8mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 3.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3m (35.54mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=85: 15, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=16.484min (inferior), t _R=19.774min (master). [α] _D ²⁵+ 44.8 (c 0.64in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.33 (s, 1H), 7.74 (t, J=9.0Hz, 1H), 7.52-7.41 (m, 3H), 7.35 (t, J=9.0Hz; 1H), 7.25 (t, J=9.0Hz, 1H), 7.12 (t, J=9.0Hz, 1H), 7.05 (d, J=6.0Hz; 1H), 4.82 (dd, J=12.0,3.0Hz, 1H), 3.58 (t, J=15.0Hz, 1H), 3.25 (d; J=15.0Hz, 1H), 2.85 (dd, J=12.0,3.0Hz, 1H), 2.53 (d, J=18Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.07,178.45,166.77,164.31,147.88,137.06; 136.72,134.94,131.65,131.58,130.90,130.52; 128.19,127.73,127.61,121.45,121.27,117.70; 116.72,59.13,50.71,48.23,46.69,42.45.HRMS:calcd.for C ₂₁H ₁₄FN ₃O ₂359.1070 the above digital proof purpose of found:359.1068. product prepares successfully.

Embodiment 22:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2d (36.0mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3n (33.75mg), yield is 90% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=22.044min (master), t _R=28.413min (inferior). [α] _D ²⁵+ 33.3 (c 0.42in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.34 (s, 1H), 7.84 (d, J=9.0Hz, 1H), 7.54-7.41 (m, 5H), 7.13 (t; J=9.0Hz, 1H), 7.05 (d, J=9.0Hz, 1H), 5.03 (dd, J=12.0,3.0Hz; 1H), 3.56 (t, J=15.0Hz, 1H), 3.27 (d, J=15.0Hz, 1H); 2.86 (dd, J=12.0,3.0Hz, 1H), 2.57 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 202.97,173.42,143.02,134.89,132.85,131.83,131.71; 130.72,130.12,128.54,126.76,125.76,123.18,112.41; 111.81,111.74,54.34,45.48,43.42,43.33,42.51.HRMS:calcd.for C ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0773. product prepares successfully.

Embodiment 23:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2e (36.0mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 3.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3o (33.75mg), yield is 90% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 98:2dr, 99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=25.076min (master), t _R=32.895min (inferior). [α] _D ²⁵+ 41.4 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.36 (s, 1H), 7.54-7.43 (m, 6H), 7.13 (t, J=8.0Hz, 1H); 7.06 (d, J=8.0Hz, 1H), 4.38 (dd, J=12.0,4.0Hz, 1H); 3.64 (t, J=16.0Hz, 1H), 3.27 (d, J=12.0Hz, 1H), 2.86 (dd; J=16.0,4.0Hz, 1H), 2.52 (d, J=16.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.24,173.44,142.69,137.67,134.02,131.66,131.21; 130.11,129.83,128.69,126.96,125.72,123.45,113.01; 111.75,109.74,54.22,46.16,45.38,43.24,42.11.HRMS:calcd.forC ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0775. product prepares successfully.

Embodiment 24:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg; 0.04mmol) and 2f (35.2mg, 0.2mmol), 1a (19.5mg; 0.1mmol), add 1mL 1, the 2-ethylene dichloride; Reacted 2.0 hours down at 80 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3p (36.73mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=44.131min (inferior), t _R=45.799min (master). [α] _D ²⁵+ 40.0 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.33 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz; 2H), 7.12 (t, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 2H); 4.27 (dd, J=16.0,4.0Hz, 1H), 3.77 (s, 3H), 3.56 (t, J=12.0Hz, 1H), 3.26 (d; J=16.0Hz, 1H), 2.81 (dd, J=16.0,4.0Hz, 1H), 2.49 (d, J=12.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.68,173.62,160.55,142.86,131.57,131.03,127.19,126.92,126.14,123.20,114.62,113.27,111.90,111.57,55.85,54.16,46.74,45.27,43.24,42.63.HRMS:calcd.forC ₂₂H ₁₇N ₃O ₃371.1270 the above digital proof purpose of found:371.1269. product prepares successfully.

Embodiment 25:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2g (32.0mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 1.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3q (35.15mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=11.205min (inferior), t _R=11.949min (master). [α] _D ²⁵+ 42.2 (c 0.46in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.33 (s, 1H), 7.49 (d, J=6.0Hz, 1H), 7.42 (t, J=9.0Hz, 1H), 7.32 (d; J=6.0Hz, 2H), 7.23 (d, J=9.0Hz, 2H), 7.13-7.03 (m, 2H), 4.27 (dd, J=15.0; 3.0Hz, 1H), 3.55 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz, 1H), 2.80 (dd; J=15.0,3.0Hz, 1H), 2.47 (d, J=15.0Hz, 1H), 2.29 (s, 3H). ¹³CNMR (75MHz, DMSO-d ₆) δ 203.64,173.58,142.88,139.60,132.34,131.58,129.85,129.65,126.92,126.13,123.18,113.18,111.83,111.59,54.24,46.59,45.55,43.24,42.43,21.34.HRMS:calcd.for C ₂₂H ₁₇N ₃O ₂355.1321 the above digital proof purpose of found:355.1320. product prepares successfully.

Embodiment 26:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2h (37.6mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3r (37.92mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=9.322min (inferior), t _R=9.681min (master). [α] _D ²⁵+ 29.5 (c 0.44in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.34 (s, 1H), 7.49 (d, J=6.0Hz, 1H), 7.44-7.28 (m, 5H); 7.14-7.04 (m, 2H), 4.28 (dd, J=12.0,3.0Hz, 1H), 3.57 (t; J=15.0Hz, 1H), 3.28 (d, J=15.0Hz, 1H), 2.92-2.80 (m, 2H); 2.48 (d, J=15.0Hz, 1H), 1.17 (d, J=6.0Hz, 6H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.65,173.58,150.24,142.90,132.54,131.59,129.76,127.23,126.90,126.13,123.46,113.19,111.84,111.61,54.26,46.51,45.57,43.28,42.47,33.79,24.35.HRMS:calcd.forC ₂₄H ₂₁N ₃O ₂383.1634 the above digital proof purpose of found:383.1632. product prepares successfully.

Embodiment 27:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2i (32.8mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 3.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3s (34.11mg), yield is 95% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 97:3dr, 98%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=13.176min (inferior), t _R=21.162min (master). [α] _D ²⁵+ 30.8 (c 0.39in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.33 (s, 1H), 7.50-7.40 (m, 4H), 7.28 (t, J=9.0Hz, 2H), 7.10 (t; J=9.0Hz, 1H), 7.05 (d, J=9.0Hz, 1H), 4.35 (dd, J=15.0,3.0Hz; 1H), 3.57 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz, 1H); 2.82 (dd, J=15.0,3.0Hz, 1H), 2.50 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.33,178.48,169.39,166.94,147.80,136.99,136.55; 131.90,131.84,130.97,128.17,121.29,121.09,118.05; 116.68,116.56,59.12,51.40,50.10,48.21,47.40.HRMS:calcd.for C ₂₁H ₁₄FN ₃O ₂359.1070 the above digital proof purpose of found:359.1069. product prepares successfully.

Embodiment 28:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg; 0.04mmol) and 2j (36.0mg, 0.2mmol), 1a (19.5mg; 0.1mmol), add 1mL 1, the 2-ethylene dichloride; Reacted 2.5 hours down at 80 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3t (34.50mg), yield is 92% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 0.3mL/min]: t with HPLC _R=28.861min (inferior), t _R=70.755min (master). [α] _D ²⁵+ 31.7 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.35 (s, 1H), 7.53-7.39 (m, 6H), 7.12-7.03 (m, 2H), 4.35 (dd, J=15.0; 3.0Hz, 1H), 3.57 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz, 1H); 2.83 (dd, J=15.0,3.0Hz, 1H), 2.50 (d, J=12.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.29,173.49,142.86,134.91,134.26,131.71,131.63,129.36,126.92,125.98,123.20,113.03,111.67,111.62,54.21,46.27,45.24,43.23,42.21.HRMS:calcd.for C ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0771. product prepares successfully.

Embodiment 29:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2k (44.8mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2.5 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3u (41.48mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 97%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=13.289min (inferior), t _R=18.891min (master). [α] _D ²⁵+ 37.1 (c 0.46in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.34 (s, 1H), 7.66 (d, J=9.0Hz, 2H), 7.49 (d, J=9.0Hz, 1H); 7.41-7.39 (m, 3H), 7.12-7.02 (m, 2H), 4.33 (dd, J=15.0,3.0Hz; 1H), 3.56 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H); 2.82 (dd, J=15.0,3.0Hz, 1H), 2.50 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.29,173.47,142.85,134.69,132.30,132.01,131.65,126.92,125.9,123.56,123.21,113.03,111.67,111.62,54.21,46.18,45.31,43.22,42.14.HRMS:calcd.forC ₂₁H ₁₄BrN ₃O ₂419.0269 the above digital proof purpose of found:419.0269. product prepares successfully.

Embodiment 30:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2l (42.8mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 3.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3v (38.86mg), yield is 95% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=6.507min (inferior), t _R=16.383min (master). [α] _D ²⁵+ 27.9 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.28 (s, 1H), 7.84 (d, J=6.0Hz, 2H), 7.69 (d, J=6.0Hz, 2H), 7.52 (d, J=9.0Hz; 1H), 7.43 (t, J=9.0Hz, 1H), 7.12 (t, J=9.0Hz, 1H), 7.05 (d, J=6.0Hz; 1H), 4.46 (dd, J=15.0,3.0Hz, 1H), 3.63 (t, J=15.0Hz, 1H), 3.28 (d; J=15.0Hz, 1H), 2.86 (dd, J=15.0,3.0Hz, 1H), 2.52 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.10,178.38,147.81,144.75,136.64,135.89,135.63; 135.32,131.90,131.84,131.19,130.88,128.20,117.89; 116.58,116.54,59.23,50.96,50.48,48.21,46.93.HRMS:calcd.forC ₂₂H ₁₄F ₃N ₃O ₂409.1038 the above digital proof purpose of found:409.1039. product prepares successfully.

The embodiment hentriaconta-:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2m (41.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3w (38.50mg), yield is 96% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 96:4dr, 98%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=15.628min (master), t _R=25.327min (inferior). [α] _D ²⁵+ 31.9 (c 0.70in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.27 (s, 1H), 7.49-7.37 (m, 3H), 7.12 (t, J=9.0Hz, 1H), 7.04 (d, J=9.0Hz; 1H), 6.64 (d, J=9.0Hz, 1H), 6.56 (s, 1H), 4.90 (dd, J=15.0,3.0Hz; 1H), 3.76 (s, 3H), 3.53 (s, 3H), 3.48 (t, J=15.0Hz, 1H), 3.22 (d; J=15.0Hz, 1H), 2.66 (dd, J=15.0,3.0Hz, 1H), 2.47 (d, J=15.0Hz, 1H). ¹³CNMR (100MHz, DMSO-d ₆) δ 208.76,178.65,166.71,163.55,147.88,136.55,134.56,131.58; 131.14,127.88,120.83,117.95,117.26,116.55,110.86,104.08; 60.95,59.18,51.19,48.35,47.34,41.37,41.27.HRMS:calcd.for C ₂₃H ₁₉N ₃O ₄401.1376 the above digital proof purpose of found:401.1378. product prepares successfully.

Embodiment 32:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg; 0.04mmol) and 2n (30.4mg, 0.2mmol), 1a (19.5mg; 0.1mmol), add 1mL 1, the 2-ethylene dichloride; Reacted 2.5 hours down at 80 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3x (32.27mg), yield is 93% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=52.525min (master). [α] _D ²⁵+ 14.7 (c 0.46in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.36 (s, 1H), 7.64 (d, J=4.0Hz, 1H), 7.48-7.42 (m, 2H), 7.29 (d; J=4.0Hz, 1H), 7.14-7.09 (m, 2H), 7.06 (d, J=8.0Hz, 1H), 4.66 (dd; J=12.0,4.0Hz, 1H), 3.44 (t, J=16.0Hz, 1H), 3.27 (d, J=16.0Hz; 1H), 3.01 (dd, J=16.0,4.0Hz, 1H), 2.52 (d, J=16.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 207.40,178.48,147.82,143.04,136.63,134.07,134.01,132.88,131.90,130.81,128.22,118.26,116.84,116.60,58.93,52.00,49.17,48.20,47.11.HRMS:calcd.forC ₁₉H ₁₃N ₃O ₂S 347.0728, and the above digital proof purpose of found:347.0727. product prepares successfully.

Embodiment 33:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2o (27.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 3.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3y (32.44mg), yield is 98% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 97:3dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 0.5mL/min]: t with HPLC _R=29.591min (master). [α] _D ²⁵+ 1.2 (c 0.51in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.38 (s, 1H), 7.77 (d, J=4.0Hz, 1H), 7.46-7.43 (m, 2H), 7.13-6.06 (m; 2H), 6.68 (d, J=4.0Hz, 1H), 6.57-6.56 (m, 1H), 4.56 (dd, J=16.0; 4.0Hz, 1H), 3.39 (t, J=16.0Hz, 1H), 3.25 (d, J=16.0Hz, 1H); 3.00 (dd, J=16.0,4.0Hz, 1H), 2.52 (d, J=16.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 207.42,178.45,154.59,149.79,149.74,147.85,136.64,131.76,130.74,128.17,118.11,116.64,116.57,115.97,58.77,49.78,48.22,45.97,45.70.HRMS:calcd.forC ₁₉H ₁₃N ₃O ₃331.0957 the above digital proof purpose of found:331.0955. product prepares successfully.

Embodiment 34:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2p (39.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL 1 to 1a; The 2-ethylene dichloride reacted 2.0 hours down at 80 ℃, and reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 4) can obtain title product 3z (35.97mg), yield is 92% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 97%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=23.053min (master), t _R=39.495min (inferior). [α] _D ²⁵-25.5 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.37 (s, 1H), 8.02-7.88 (m, 4H), 7.76 (d, J=9.0Hz, 1H), 7.65 (t, J=9.0Hz; 1H), 7.55-7.38 (m, 3H), 7.28 (t, J=9.0Hz, 1H), 7.11 (d, J=9.0Hz, 1H); 5.44 (dd, J=15.0,3.0Hz, 1H), 3.73 (t, J=15.0Hz, 1H), 3.35 (d, J=15.0Hz; 1H), 2.92 (dd, J=15.0,3.0Hz, 1H), 2.62 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.58,173.59,143.17,134.17,131.99,131.84,131.48; 130.57,129.57,127.10,126.96,126.89,126.78; 126.28,125.96,123.46,123.40,113.01,112.05; 111.88,54.72,46.30,43.43,43.40,38.43.HRMS:calcd.for C ₂₅H ₁₇N ₃O ₂391.1321 the above digital proof purpose of found:391.1324. product prepares successfully.

Embodiment 35:

Pack into successively in the reaction flask quinine butylamine I (6.5mg, 0.02mmol), additive A 6 (13.9mg; 0.04mmol) and 2a (29.2mg, 0.2mmol), 1a (19.5mg; 0.1mmol), adding 1mL toluene, reaction was reacted 1.5 hours down in 1.0 hours or 110 ℃ under 100 ℃; Reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying, removes and desolvates; (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3a (33.8mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 95.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=13.352min (inferior); t _R=14.108min (master). [α] _D ²⁵+ 27.4 (c 0.5in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.30 (s, 1H), 7.51-7.40 (m, 7H), 7.10 (t, J=9.0Hz, 1H); 7.03 (d, J=6.0Hz, 1H), 4.30 (dd, J=12.0,3.0Hz, 1H); 3.58 (t, J=15.0Hz, 1H), 3.25 (d, J=15.0Hz, 1H), 2.82 (dd; J=12.0,3.0Hz, 1H), 2.49 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.56,178.51,147.82,140.30,136.59,135.03,134.80,134.29,131.90,131.06,128.18,118.12,116.74,116.55,59.23,51.39,50.78,48.22,47.29.HRMS:calcd.for C ₂₁H ₁₅N ₃O ₂341.1164 the above digital proof purpose of found:341.1162. product prepares successfully.

Embodiment 36:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (22.5mg 0.1mmol), adds 1mL toluene to 1d; Reacted 1.5 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3d (36.73mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr, 95.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=14.525min (master); t _R=19.332min (inferior). [α] _D ²⁵+ 93.1 (c 0.50in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.14 (s, 1H), 7.51-7.34 (m, 5H), 7.05-6.95 (m, 3H), 4.31 (dd, J=12.0; 3.0Hz, 1H), 3.75 (s, 3H), 3.55 (t, J=15.0Hz, 1H), 3.24 (d; J=15.0Hz, 1H), 2.86 (d, J=15.0Hz, 1H), 2.46 (d, J=12.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.65,173.32,155.83,136.00,135.37,135.24,129.93,129.23,127.31,115.54,114.62,113.19,112.00,111.77,56.41,54.66,46.40,45.69,43.28,42.20.HRMS:calcd.for C ₂₂H ₁₇N ₃O ₃371.1270 the above digital proof purpose of found:371.1272. product prepares successfully.

Embodiment 37:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (27.3mg 0.1mmol), adds 1mL toluene to 1i; Reacted 2.0 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3i (41.06mg), yield is 98% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 99:1dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 0.3mL/min]: t with HPLC _R=47.014min (inferior); t _R=48.351min (master). [α] _D ²⁵+ 62.9 (c 0.5in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.51 (s, 1H), 7.50-7.44 (m, 6H), 7.32-7.29 (m, 1H), 7.26-7.15 (m, 1H); 4.27 (dd, J=15.0,3.0Hz, 1H), 3.59 (t, J=15.0Hz, 1H), 3.26 (d; J=9.0Hz, 1H), 2.81 (d, J=12.0Hz, 1H), 2.57 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.37,173.46,144.62,135.19,130.11,129.82,129.34,128.74,125.81,125.40,124.69,114.43,113.01,111.55,54.20,46.27,45.81,42.90,42.31.HRMS:calcd.for C ₂₁H ₁₄BrN ₃O ₂419.0269 the above digital proof purpose of found:419.0271. product prepares successfully.

Embodiment 38:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2a (29.2mg; 0.2mmol), (26.3mg 0.1mmol), adds 1mL toluene to 1k; Reacted 1.5 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3k (39.26mg), yield is 96% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 95:5dr, 97.0%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=70: 30, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=12.604min (inferior); t _R=18.547min (master). [α] _D ²⁵-8.7 (c 0.45in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.79 (s, 1H), 7.81-7.73 (m, 2H), 7.56-7.39 (m, 5H), 7.32-7.26 (m, 1H), 4.30 (dd; J=12.0,3.0Hz, 1H), 3.61 (t, J=15.0Hz, 1H), 3.26 (d, J=15.0Hz; 1H), 2.81 (dd, J=15.0,3.0Hz, 1H), 2.69 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 203.41,174.20,140.52,135.15,130.92,130.15,129.83,129.35; 128.03,125.22,123.33,123.28,122.51,112.88,112.75; 112.42,111.44,53.44,46.48,45.68,42.58,42.28.HRMS:calcd.forC ₂₂H ₁₄F ₃N ₃O ₂409.1038 the above digital proof purpose of found:409.1037. product prepares successfully.

Embodiment 39:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2d (36.0mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL toluene to 1a; Reacted 2.5 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3n (36.37mg), yield is 97% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 97:3dr,＞99%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=24.393min (master); t _R=30.762min (inferior). [α] _D ²⁵+ 32.9 (c 0.66in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.34 (s, 1H), 7.84 (d, J=9.0Hz, 1H), 7.54-7.41 (m, 5H), 7.13 (t; J=9.0Hz, 1H), 7.05 (d, J=9.0Hz, 1H), 5.03 (dd, J=12.0,3.0Hz; 1H), 3.56 (t, J=15.0Hz, 1H), 3.27 (d, J=15.0Hz, 1H); 2.86 (dd, J=12.0,3.0Hz, 1H), 2.57 (d, J=15.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 202.97,173.42,143.02,134.89,132.85,131.83,131.71; 130.72,130.12,128.54,126.76,125.76,123.18,112.41; 111.81,111.74,54.34,45.48,43.42,43.33,42.51.HRMS:calcd.for C ₂₁H ₁₄ClN ₃O ₂375.0775 the above digital proof purpose of found:375.0773. product prepares successfully.

Embodiment 40:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2l (42.8mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL toluene to 1a; Reacted 2.5 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3v (38.86mg), yield is 95% to crude product through simple column chromatography.

Product is analyzed, and the result is following: 97:3dr, 97%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=80: 20, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=6.706min (inferior); t _R=15.554min (master). [α] _D ²⁵+ 26.5 (c 0.45in acetone). ¹H NMR (300MHz, DMSO-d ₆) δ 11.28 (s, 1H), 7.84 (d, J=6.0Hz, 2H), 7.69 (d, J=6.0Hz, 2H), 7.52 (d, J=9.0Hz; 1H), 7.43 (t, J=9.0Hz, 1H), 7.12 (t, J=9.0Hz, 1H), 7.05 (d, J=6.0Hz; 1H), 4.46 (dd, J=15.0,3.0Hz, 1H), 3.63 (t, J=15.0Hz, 1H), 3.28 (d; J=15.0Hz, 1H), 2.86 (dd, J=15.0,3.0Hz, 1H), 2.52 (d, J=15.0Hz, 1H). ¹³C NMR (100MHz, DMSO-d ₆) δ 208.10,178.38,147.81,144.75,136.64,135.89,135.63; 135.32,131.90,131.84,131.19,130.88,128.20,117.89; 116.58,116.54,59.23,50.96,50.48,48.21,46.93.HRMS:calcd.forC ₂₂H ₁₄F ₃N ₃O ₂409.1038 the above digital proof purpose of found:409.1039. product prepares successfully.

Embodiment 41:

Pack into successively in the reaction flask quinine butylamine (6.5mg, 0.02mmol), R-BINOL phosphoric acid (13.9mg, 0.04mmol) and 2f (35.2mg; 0.2mmol), (19.5mg 0.1mmol), adds 1mL toluene to 1a; Reacted 1.4 hours down at 100 ℃, reaction system is used ethyl acetate extraction, and organic layer is used anhydrous sodium sulfate drying; Remove and desolvate, (eluent is an ETHYLE ACETATE: sherwood oil=1: 3) can obtain title product 3p (36.73mg), yield is 99% to crude product through simple column chromatography.

Product is analyzed, and the result is following:＞99:1dr, 98%ee. measures [Daicel Chiralpak AD-H, hexane/i-PrOH=90: 10, λ=254nm, flow velocity 1.0mL/min]: t with HPLC _R=44.576min (inferior); t _R=46.099min (master). [α] _D ²⁵+ 39.7 (c 0.50in acetone). ¹H NMR (400MHz, DMSO-d ₆) δ 11.33 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz; 2H), 7.12 (t, J=8.0Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 2H); 4.27 (dd, J=16.0,4.0Hz, 1H), 3.77 (s, 3H), 3.56 (t, J=12.0Hz, 1H), 3.26 (d; J=16.0Hz, 1H), 2.81 (dd, J=16.0,4.0Hz, 1H), 2.49 (d, J=12.0Hz, 1H). ¹³C NMR (75MHz, DMSO-d ₆) δ 203.68,173.62,160.55,142.86,131.57,131.03,127.19,126.92,126.14,123.20,114.62,113.27,111.90,111.57,55.85,54.16,46.74,45.27,43.24,42.63.HRMS:calcd.forC ₂₂H ₁₇N ₃O ₃371.1270 the above digital proof purpose of found:371.1269. product prepares successfully.

Claims

A chirality 2 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives is characterized in that, its chemical structural formula is:

In the formula, the R substituting group is selected from: a kind of in hydrogen, halogen, methyl, methoxyl group or the trifluoromethoxy; Aryl Ar is selected from: phenyl, to fluorophenyl, rubigan, to bromophenyl, p-methoxyphenyl, p-methylphenyl, p-isopropyl phenyl, p-trifluoromethyl phenyl, adjacent fluorophenyl, Chloro-O-Phenyl, o-methoxyphenyl, 2, a kind of in 4-dimethoxy phenyl, a chloro-phenyl-, 1-naphthyl, 2-furans or the 2-thienyl.
According to the said chirality 2 of claim 1 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2; 2-two carbonitrile derivatives is characterized in that, when said chirality 2 '; 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the chemical structural formula of 2-two carbonitrile derivatives is:

When
, the R substituting group is selected from: a kind of in hydrogen, 4-chlorine, 4-bromine, 5-methyl, 5-bromine, 5-chlorine, 5-fluorine, 5-methoxyl group, 6-bromine or the 7-trifluoromethyl.
According to the said chirality 2 of claim 1 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2; 2-two carbonitrile derivatives is characterized in that, when chirality 2 '; 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the chemical structural formula of 2-two carbonitrile derivatives is:

When
, R is a fluorine.
The said chirality 2 of claim 1 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2; The preparation method of 2-two carbonitrile derivatives is characterized in that: with isatin propane dinitrile condenses and methyl aryl α, beta-unsaturated carbonyl compound is a reaction substrate; In the presence of catalyzer and additive, through two Michael reactions, prepare chirality 2 '; 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives; Wherein, said isatin propane dinitrile condenses is selected from:

Said methyl aryl α, the chemical structural formula of beta-unsaturated carbonyl compound is:

Said catalyzer is selected from:

Said additive is selected from: a kind of in phenylformic acid, p-Nitrobenzenecarboxylic acid, trifluoroacetic acid, Boc-L-phenylglycine, Boc-D-phenylglycine, R-BINOL phosphoric acid or the S-BINOL phosphoric acid.
The said chirality 2 of claim 4 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the preparation method of 2-two carbonitrile derivatives is characterized in that: said catalyst consumption is the 5-20% of isatin propane dinitrile condenses amount of substance.
The said chirality 2 of claim 4 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the preparation method of 2-two carbonitrile derivatives is characterized in that: the consumption of said additive is the 10-40% of isatin propane dinitrile condenses amount of substance.
The said chirality 2 of claim 4 ', 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2, the preparation method of 2-two carbonitrile derivatives; It is characterized in that, specifically may further comprise the steps: with 1,2-ethylene dichloride or toluene are solvent; With isatin propane dinitrile condenses and methyl aryl α, beta-unsaturated carbonyl compound is a reaction substrate, in the presence of catalyzer and additive; Through two Michael reactions, in 25～110 ℃ of down reactions more than 1.0 hours, make 2 '; 5-dicarbapentaborane-3-aryl spiral shell [hexanaphthene-1,3 '-indoles]-2,2-two carbonitrile derivatives.