CN114621158A

CN114621158A - Benzoxazine compound and synthesis method and application thereof

Info

Publication number: CN114621158A
Application number: CN202210288871.2A
Authority: CN
Inventors: 李鹏飞; 陈续玲; 王韬; 高爽; 马保德; 欧阳凌云; 张绪穆
Original assignee: Southern University of Science and Technology
Current assignee: Southern University of Science and Technology
Priority date: 2022-03-22
Filing date: 2022-03-22
Publication date: 2022-06-14
Also published as: CN116120253A

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a benzoxazine compound, which has a structure shown in a general formula I:

wherein R is¹Is alkyl or benzyl; r²Is hydrogen, alkyl or halogen; r³Selected from phenyl, phenyl substituted by halogen, alkyl or alkoxy, naphthyl, furyl, thienyl, alkyl. The invention also discloses a synthetic method of the benzoxazine compound, which has the advantages that: the yield is high (63-98%); one-pot methodSynthesis without stepwise reaction; protecting raw materials without protecting groups such as Boc and the like; the reaction condition is mild, and the reaction can be carried out at room temperature. Enantioselectivity [4+2] of 4H-benzoxazine Compounds with isocyanates Using organophosphine catalysis]And performing cycloaddition reaction to construct chiral 3, 4-dihydroquinazoline-2-ketone compounds with various structures.

Description

Benzoxazine compound and its synthesis method and use

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a benzoxazine compound and a synthesis method and application thereof.

Background

The Morita-Baylis-Hillman (MBH) reaction has simple and convenient operation, simple raw materials, mild reaction conditions and high efficiency, and is an important reaction for forming carbon-carbon bonds; and simultaneously, functional groups such as double bonds, ester groups or nitro groups can be introduced into target molecules, which lays a foundation for subsequent functional group conversion. With the intensive studies on the MBH reaction, MBH adducts, which are products of the MBH reaction, have also been attracting attention. The compound has a plurality of functional groups and a plurality of reaction sites, and is widely applied to organic catalytic asymmetric allyl alkylation and [3+ n ], [1+4] cyclization reactions as a general synthon. However, the structure of the MBH adduct is limited to the aldehyde and isatin skeleton, and the reaction site is unchanged, resulting in curing of the reaction type. Currently, there are few reports on the asymmetric reactions of the novel MBH adducts catalyzed organically. Therefore, the development of a new MBH addition product and a related organic catalytic asymmetric reaction not only can enrich the reaction types of the MBH addition product, but also can promote the application of the compound in asymmetric organic synthesis; has very important significance.

Disclosure of Invention

The invention aims to provide a benzoxazine compound with a novel structure.

It is another object of the present invention to provide a method for synthesizing the benzoxazine compound.

Another object of the present invention is to provide uses of the benzoxazine compound: constructing chiral 3, 4-dihydroquinazoline-2 ketone compounds.

In order to achieve one of the purposes, the invention adopts the following technical scheme:

the design idea of the invention is to introduce ester groups on carbon-carbon double bonds in vinyl 4H-benzo [1,3] oxazine molecules and modify the molecules into novel MBH addition compounds. The introduction of the ester group improves the reaction activity of vinyl double bonds, and the vinyl double bonds can be attacked by a chiral nucleophilic organic catalyst to form dipoles with nitrogen anion nucleophilic sites, and then the dipoles and the dipoles are subjected to asymmetric cyclization to obtain a novel chiral cyclic compound.

A benzoxazine compound having the structure of formula i:

wherein R is¹Is alkyl or benzyl;

R²is hydrogen, alkyl or halogen;

R³selected from phenyl, phenyl substituted by halogen, alkyl or alkoxy, naphthyl, furyl, thienyl, alkyl.

Further, said R¹Is (C1-C4) alkyl or benzyl.

Further, said R¹Selected from methyl, ethyl, n-butyl, isobutyl, tert-butyl and benzyl.

Further, said R²Hydrogen, (C1-C4) alkyl or halogen.

Further, said R²Selected from hydrogen, methyl, fluorine, chlorine, bromine.

Further, said R³Selected from phenyl, naphthyl, furyl, thienyl, alkyl substituted by halogen, alkyl or alkoxy.

Further, said R³Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, (C1-C4) alkyl-substituted phenyl, (C1-C4) alkoxy-substituted phenyl, naphthyl, furyl, thienyl, and (C1-C4) alkyl.

Further, said R³Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, methoxy-substituted phenyl, methyl-substituted phenyl, naphthyl, furyl, thienyl, (C1-C4) alkyl.

Further, said R³Selected from 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1-naphthyl, 2-furyl, 2-thienyl, n-butyl.

Further, said R³Selected from naphthyl, furyl, thienyl and (C1-C4) alkyl.

Further, said R³Selected from 1-naphthyl, 2-furyl, 2-thienyl and n-butyl.

Further, the benzoxazine compound is selected from the following compounds:

a method of synthesizing a benzoxazine compound comprising the steps of: compound M1 is reacted as follows in the presence of di-tert-butyl dicarbonate and a catalyst

Wherein R is¹、R²、R³As described above; the catalyst is 1, 4-diazabicyclo [2.2.2]Octane or 4-dimethylaminopyridine.

Further, the molar ratio of the compound M1 to di-tert-butyl dicarbonate is 1: (1-3).

Further, the amount of the catalyst used was 10 mol% or more (relative to compound M1).

Further, the reaction takes toluene, dichloromethane, chloroform, ethyl acetate or acetonitrile as a solvent.

Further, the temperature of the reaction is above 20 ℃, and the time of the reaction is at least 24 h.

The application of the benzoxazine compound in synthesizing chiral quinazolinone: reacting compound I with compound M2 using a chiral phosphine catalyst to obtain a chiral quinazolinone compound:

wherein R is¹、R²、R³As described above; ar is selected from phenyl substituted by halogen, alkyl or alkoxy; the chiral phosphine catalyst is one of the following:

further, Ar is selected from phenyl substituted by halogen, (C1-C4) alkyl or (C1-C4) alkoxy.

Further, Ar is selected from phenyl substituted with halogen, methyl or methanoxy.

Further, Ar is selected from 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 3-methylphenyl.

Further, the molar ratio of compound i to compound M2 is 1: (1-3).

Further, the amount of the chiral phosphine catalyst is more than 10 mol% (relative to the compound I).

Further, the reaction takes toluene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate or acetonitrile as a solvent.

Further, the reaction temperature is above-5 ℃, and the reaction time is at least 24 h.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.

As used herein, "alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), where alkyl, cycloalkyl are defined herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by an oxygen bridge. Alkoxy also includes substituted alkoxy. Alkoxy groups may be optionally substituted one or more times with halo.

As used herein, "halogen" refers to fluorine, chlorine, bromine and iodine.

"benzyl" as used herein refers to PhCH₂-。

The "substitution" of the "substituted phenyl" or "substituted phenyl" as described herein may be mono-or polysubstituted; "substituted phenyl" or "substituted phenyl" includes: (1) the phenyl ring has a non-hydrogen substituent; (2) the benzene ring has two or more non-hydrogen substituents which may be the same or different. The substituted position may be any of positions of benzene rings 2, 3,4, 5, 6.

"naphthyl" means

Including 1-naphthyl and 2-naphthyl.

"furyl" includes 2-furyl, 3-furyl.

"thienyl" includes 2-thienyl, 3-thienyl.

The invention has the following beneficial effects:

the MBH addition product has a novel structural framework, and can be further converted into chiral 3, 4-dihydroquinazoline-2 ketone compounds.

The synthesis method of the invention is to use diazabicyclo [2.2.2]In the presence of octane, MBH alcohol is first reacted with Boc₂The reaction of O to form MBH carbonate and subsequent intramolecular cyclization to obtain 4H-benzoxazine compound has the advantages of: the yield is high (63-98%); the synthesis is carried out by a one-pot method, and the economy is realized; step-by-step reaction is not needed, the operation is simple, and the practicability is strong; the raw material does not need to be protected by a protecting group such as BocIs simple and easy to obtain; the reaction condition is mild, and the reaction can be carried out at room temperature; the substrate has wide range and contains various electron-withdrawing or electron-donating substituents.

The 4H-benzoxazine compound and isocyanate are subjected to enantioselective [4+2] cycloaddition reaction under the catalysis of organic phosphine, so that chiral 3, 4-dihydroquinazoline-2 ketone compounds with various structures can be constructed, the reaction yield is high, the enantioselectivity is good, and the reaction conditions are mild.

Detailed Description

Unless otherwise indicated, starting materials and solvents were commercially available without further purification. Thin Layer Chromatography (TLC) used 60F254 silica gel plates, 254 and 365nm uv light. Silica gel with the particle size of 300-400 meshes is used for silica gel column chromatography. The NMR spectra were recorded using a Brucker-400MHz NMR spectrometer with chemical shifts in ppm and coupling constants in Hz. High Resolution Mass Spectrometry (HRMS) uses ESI ionization. High performance liquid chromatography analysis used Agilent 1200 (UV detection at 254 nm). Chiralpak IF-3, IB column was purchased from Daicel chemical industries, Inc. Optical rotation was measured using Rudolph Research Analytical (Atopol I).

Example 1

Synthesis of starting materials

Step 1: at 0 ℃ to LiAlH₄(60mmol, 2.0 equiv.) in THF (60mL) was added dropwise a solution of substituted 2-aminobenzoic acid (30mmol, 1.0 equiv.) in THF (60mL) and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was complete, the mixture was hydrolyzed by the addition of water (6mL) and 5 wt% NaOH solution (10.0 mL). The suspension was filtered and the residue was washed with EtOAc. The organic phase was washed successively with water and saturated aqueous NaCl solution, anhydrous Na₂SO₄Drying, concentration under reduced pressure and purification by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) gave the product S2.

Step 2: to S2(20mmol, 1.0 equiv.) and Et at 0 deg.C₃N (40mmol, 2.0 equiv.) in THF (100mL) was added slowlyR³COCl (20.0mmol, 1.0 equiv.). After completion, the mixture was gradually warmed to room temperature and stirred for 12 hours. The solvent was removed under reduced pressure and the crude product S3 was used directly in the next reaction without further purification.

And step 3: a500 mL round bottom flask was charged with S3(20mmol, 1.0 equiv.), PCC (pyridinium chlorochromate, 30mmol, 1.5 equiv.), and DCM (250mL), and the mixture was stirred at room temperature for 24 hours, after which it was filtered through celite. Concentration gave the crude product which was then purified by silica gel column chromatography (petroleum ether/ethyl acetate 20:1) to give product S4.

And 4, step 4: a250 mL round bottom flask was charged with S4(10mmol,1.0 equiv.), DABCO (10mmol,1.0 equiv.), N (C)₂H₄OH)₃(8mmol,0.8 equiv.), THF (100mL), and methyl acrylate (30mmol, 3.0 equiv.). After stirring at room temperature for 72 h, the mixture was concentrated and dissolved in DCM (50mL) and then sequentially with saturated NaHCO₃Washing with aqueous solution, saturated NaCl aqueous solution, and anhydrous Na₂SO₄Drying, removal of solvent and purification of the residue by silica gel column chromatography (petroleum ether/ethyl acetate 4:1) gave product 1.

Example 2

The benzoxazine compound 2a was obtained in 47% yield under 4-Dimethylaminopyridine (DMAP) conditions using MBH alcohol 1a as a substrate. By substitution of 1, 4-diazabicyclo [2.2.2]Octane (DABCO) as Lewis base catalyst gave the product 2a in 96% yield. The solvent and the catalyst are screened, and the optimal reaction conditions are determined: MBH alcohol 1a (0.1mmol), Boc₂O (0.15mmol), DABCO (20 mol%) and CH₂Cl₂(0.5mL) of the mixed system was reacted at room temperature for 24 hours.

TABLE 1

Reaction conditions are as follows: 1a (0.1mmol), Boc₂The mixture of O (0.15mmol) and catalyst (20 mmol%) in solvent (0.5mL) was stirred at Room Temperature (RT) for 24 h.

Compound 2a characterization data:

yellow oil, 28.1mg, 96% yield.¹H NMR(400MHz,CDCl₃)δ8.23–8.01(m,2H),7.52–7.46(m,1H),7.46–7.39(m,2H),7.39–7.30(m,2H),7.20(m,J＝7.5,4.3Hz,1H),7.04(m,J＝7.5,0.9Hz,1H),6.44(d,J＝11.6Hz,2H),5.53(s,1H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.9,156.2,139.5,138.9,132.5,131.6,129.5,128.4,128.1,126.7,125.3,125.2,123.1,73.6, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₆NO₃) m/z 294.1125, found m/z 294.1124.

Examples 2 to 27 extended the substrate. The synthesis method is suitable for MBH alcohol 1 with various substituent groups, and the reaction yield is generally high. Having different ester groups (CO)₂R¹) The MBH alcohol 1a-e is obtained with the yield of 82-96%; when R1 is benzyl Bn, the yield is moderate (63%); both electron withdrawing groups (F, Cl, Br) and electron donating groups (Me, MeO) can be introduced into the substituent (R)³) In the aromatic ring, the product is obtained with a yield of 81-98%; the product is obtained by the 1-naphthyl and heteroaryl with large steric hindrance in 81-87% yield; the yield of the MBH alcohol containing the aliphatic substituent is 71 percent; substituent R²The electronic properties and positions of (A) have almost no influence on the reaction, and the yield of the corresponding product is 81-95%. These results indicate that the method of the present invention is a synthesis of 4H-benzo [ d ]][1,3]An efficient method for oxazine compounds.

To a solution of compound 1(0.1mmol,1.0 eq) and DABCO (0.02mmol,0.2 eq) in DCM (0.5mL) was added slowly (Boc)₂O (0.15mmol,1.5 equiv.). After stirring at room temperature for 24 hours, the reaction mixture was successively diluted with dilute hydrochloric acid (1mol/L) and saturated NaHCO₃Aqueous solution, saturated NaClThe aqueous solution was washed, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to obtain product 2.

Example 3

Compound 2b characterization data: yellow oil, 28mg, 91% yield.¹H NMR(400MHz,CDCl₃)δ8.16–8.06(m,2H),7.53–7.46(m,1H),7.45–7.38(m,2H),7.39–7.32(m,2H),7.20(m,J＝7.5,5.4,3.3Hz,1H),7.07–7.00(m,1H),6.44(d,J＝13.4Hz,2H),5.52(s,1H),4.29(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.5,156.3,139.5,139.2,132.6,131.6,129.5,129.3,128.4,128.2,126.7,125.3,125.2,123.2,73.8,61.4, 14.3. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₃) m/z for 308.1281, found m/z 308.1277.

Example 4

Compound 2c characterization data: yellow oil, 30.6mg, 91% yield.¹H NMR(400MHz,CDCl₃)δ8.23–7.98(m,2H),7.52–7.46(m,1H),7.42(m,J＝7.4,1.7Hz,2H),7.38–7.33(m,2H),7.20(m,J＝7.4,5.4,3.3Hz,1H),7.06–7.00(m,1H),6.44(d,J＝12.8Hz,2H),5.52(s,1H),4.24(t,J＝6.6Hz,2H),1.71–1.61(m,2H),1.43–1.31(m,2H),0.92(t,J＝7.4Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.6,156.3,139.5,139.2,132.6,131.6,129.5,129.3,128.4,128.1,126.7,125.3,125.2,123.2,73.9,65.3,30.8,19.3, 13.8. HRMS accurate mass calculation [ M + H]⁺(C₂₁H₂₂NO₃) m/z for 336.1594, found m/z 336.1589.

Example 5

Compound 2d characterization data: yellow oil, 28.0mg, 84% yield.¹H NMR(400MHz,CDCl₃)δ8.16–7.93(m,2H),7.52–7.45(m,1H),7.45–7.39(m,2H),7.37–7.32(m,2H),7.20(m,J＝7.6,5.0,3.6Hz,1H),7.04(d,J＝7.4Hz,1H),6.45(d,J＝8.4Hz,2H),5.53(s,1H),4.02(d,J＝6.6Hz,2H),1.98(m,J＝13.4,6.7Hz,1H),0.93(d,J＝6.7Hz,6H)。¹³C NMR(101MHz,CDCl₃) δ 165.6,156.3,139.5,139.2,132.7,131.6,129.5,129.4,128.4,128.2,126.7,125.3,125.2,123.2,73.9,71.5,27.9,19.2, 19.2. HRMS accurate mass calculation [ M + H]⁺(C₂₁H₂₂NO₃) m/z for 336.1594, found m/z 336.1591.

Example 6

Compound 2e characterization data: yellow oil, 27.6mg, 82% yield.¹H NMR(400MHz,CDCl₃)δ8.21–8.00(m,2H),7.51–7.45(m,1H),7.45–7.38(m,2H),7.37–7.29(m,2H),7.22–7.14(m,1H),7.02(m,J＝7.6,1.1Hz,1H),6.41(s,1H),6.32(s,1H),5.44(s,1H),1.49(s,9H)。¹³C NMR(101MHz,CDCl₃) δ 164.7,156.3,140.5,139.5,132.7,131.5,129.4,128.3,128.1,126.6,125.2,125.1,123.4,81.8,74.1,28.1, 27.5. HRMS accurate mass calculation [ M + H]⁺(C₂₁H₂₂NO₃) m/z for 336.1594, found m/z 336.1592.

Example 7

Characterization data for compound 2 f: yellow oil, 23.1mg, 63% yield.¹H NMR(400MHz,CDCl₃)δ8.19–7.90(m,2H),7.52–7.43(m,1H),7.43–7.29(m,9H),7.19(m,J＝7.5,5.7,2.9Hz,1H),7.05–6.99(m,1H),6.47(s,2H),5.52(s,1H),5.46–5.15(m,2H)。¹³C NMR(101MHz,CDCl₃) δ 165.4,156.3,139.5,138.9,135.7,132.6,131.6,123.0,129.6,128.8,128.5,128.4,128.4,128.2,126.8,125.3,125.3,123.0,73.7, 67.1. HRMS accurate mass calculation [ M + H]⁺(C₂₄H₂₀NO₃) m/z for 370.1438, found m/z 370.1433.

Example 8

Characterization data for compound 2 g: yellow oil, 28.5mg, 92% yield.¹H NMR(400MHz,CDCl₃)δ8.13–7.91(m,2H),7.43–7.37(m,2H),7.37–7.30(m,2H),7.20(m,J＝7.3,2.0Hz,1H),7.05–7.00(m,1H),6.43(d,J＝3.9Hz,2H),5.51(s,1H),3.83(s,3H)。¹³C NMR(126MHz,CDCl₃)δ165.9,163.9(J_CF＝257.9Hz),155.3,139.2,138.8,137.8,131.1,129.7(J_CF＝10.5Hz),129.4,128.7,127.0,125.3(J_CF＝3.2Hz),122.9,115.5(J_CF21.8Hz),73.8, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅FNO₃) m/z 312.1030, found m/z 312.1024.

Example 9

Compound 2h characterization data: yellow oil, 30.4mg, 93% yield.¹H NMR(400MHz,CDCl₃)δ8.06–7.98(m,2H),7.44–7.37(m,2H),7.36–7.30(m,2H),7.21(m,J＝7.2,1.9Hz,1H),7.03(m,J＝7.6,1.2Hz,1H),6.43(d,J＝4.0Hz,2H),5.51(s,1H),3.83(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.9,155.3,139.3,138.8,137.9,131.1,129.8,129.3,128.7,127.0,125.3,123.0,73.8, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅ClNO₃) m/z 328.0735, found m/z 328.0733.

Example 10

Characterization data for compound 2 i: yellow oil, 34.8mg, 94% yield.¹H NMR(400MHz,CDCl₃)δ8.11–7.87(m,2H),7.59–7.51(m,2H),7.40–7.29(m,2H),7.21(m,J＝7.1,1.9Hz,1H),7.06–6.99(m,1H),6.43(d,J＝3.8Hz,2H),5.51(s,1H),3.83(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.9,155.4,139.3,138.8,131.7,131.6,129.7,129.6,127.0,127.0,126.4,125.3,125.3,123.0,73.8, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅BrNO₃) m/z 372.0230, found m/z 372.0224.

Example 11

Compound 2j characterization data: yellow oil, 24.7mg, 81% yield.¹H NMR(400MHz,CDCl₃)δ8.18–7.82(m,2H),7.38–7.31(m,2H),7.24(s,1H),7.22(s,1H),7.18(m,J＝7.5,6.0,2.6Hz,1H),7.06–7.01(m,1H),6.42(d,J＝8.3Hz,2H),5.52(d,J＝1.1Hz,1H),3.84(s,3H),2.40(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.1,156.5,142.2,139.7,139.0,129.8,129.5,129.4,129.2,128.2,126.5,125.3,125.2,123.2,73.57,52.4, 21.7. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₃) m/z 308.1281, found m/z 308.1276.

Example 12

Compound 2k characterization data: yellow oil, 30.8mg, 96% yield.¹H NMR(400MHz,CDCl₃)δ8.09–8.00(m,2H),7.40–7.28(m,2H),7.17(m,J＝7.1,2.1Hz,1H),7.09–6.99(m,1H),6.97–6.86(m,2H),6.41(d,J＝2.5Hz,2H),5.51(s,1H),3.85(s,3H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.1,162.6,156.3,139.8,138.9,130.0,129.5,129.4,126.3,125.3,125.0,125.0,123.1113.8, 73.5,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₄) m/z 324.1230, found m/z 324.1226.

Example 13

Characterization data for compound 2 l: yellow oil, 26.4mg, 82% yield.¹H NMR(400MHz,CDCl₃)δ7.71–7.62(m,2H),7.35(m,J＝3.7,1.0Hz,2H),7.32(d,J＝7.9Hz,1H),7.20(m,J＝7.5,5.0,3.6Hz,1H),7.04(m,J＝8.2,1.1Hz,2H),6.43(d,J＝7.2Hz,2H),5.52(s,1H),3.87(s,3H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.0,159.7,156.2,139.5,138.9,134.0,129.5,129.4,126.8,125.3,125.2,123.1,120.7,118.3,112.6,73.7,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₄) m/z 324.1230, found m/z 324.1226.

Example 14

Characterization data for compound 2 m: yellow oil, 28.8mg, 94% yield.¹H NMR(400MHz,CDCl₃)δ8.09–7.87(m,2H),7.38–7.32(m,2H),7.24(d,J＝1.7Hz,1H),7.22(s,1H),7.19(m,J＝7.4,5.9,2.8Hz,1H),7.06–6.93(m,1H),6.42(d,J＝8.4Hz,2H),5.52(s,1H),3.84(s,3H),2.40(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.0,156.5,142.1,139.6,138.9,129.8,129.5,129.4,129.2,128.2,126.5,125.3,125.2,123.2,73.5,52.4, 21.7. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₃) m/z 308.1281, found m/z 308.1276.

Example 15

Characterization data for compound 2 n: yellow oil, 31.4mg, 98% yield.¹H NMR(400MHz,CDCl₃)δ7.71–7.62(m,2H),7.35(m,J＝3.8,0.9Hz,2H),7.32(d,J＝7.9Hz,1H),7.20(m,J＝7.4,4.9,3.6Hz,1H),7.04(m,J＝8.3,1.2Hz,2H),6.43(d,J＝7.3Hz,2H),5.52(s,1H),3.87(s,3H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.0159.7,156.2,139.5,138.9,134.0129.6,129.4,126.8,125.3,125.3,123.1,120.7,118.3,112.6, 73.7,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₄) m/z 324.1230, found m/z 324.1225.

Example 16

Compound 2o characterization data: yellow oil, 29.1mg, 87% yield.¹H NMR(400MHz,CDCl₃)δ9.01(m,J＝8.6,1.1Hz,1H),7.96(m,J＝8.1,3.9,1.1Hz,2H),7.90–7.84(m,1H),7.59(m,J＝8.5,6.8,1.5Hz,1H),7.55–7.49(m,2H),7.49–7.43(m,1H),7.40(m,J＝7.6,1.5Hz,1H),7.33–7.19(m,1H),7.10–6.97(m,1H),6.55(d,J＝7.3Hz,2H),5.66(s,1H),3.87(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.0,157.1,139.3,138.9,134.1,131.9,131.3,130.3,129.8,129.6,129.0,128.6,127.2,127.1,126.2,126.1,125.4,125.1,124.9,122.8,74.0, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₂H₁₈NO₃) m/z 344.1281, found m/z 344.1278.

Example 17

Compound 2p characterization data: yellow oil, 22.9mg, 81% yield.¹H NMR(400MHz,CDCl₃)δ7.59(s,1H),7.36(m,J＝15.1,7.7Hz,2H),7.19(t,J＝7.3Hz,1H),7.07–6.97(m,2H),6.55–6.48(m,1H),6.44(s,1H),6.38(s,1H),5.56(s,1H),3.83(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.8,149.2,146.6,145.9,138.8,138.6,129.8,129.7,126.9,125.4,125.3,123.1,115.2,112.0,73.6, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₆H₁₄NO₄) m/z 284.0917, found m/z 284.0914.

Example 18

Compound 2q characterization data: yellow oil, 28.2mg, 87% yield.¹H NMR(400MHz,CDCl₃)δ7.68(m,J＝3.7,1.2Hz,1H),7.48(m,J＝5.0,1.2Hz,1H),7.39–7.28(m,2H),7.18(m,J＝7.2,1.7Hz,1H),7.08(m,J＝5.0,3.7Hz,1H),7.02(d,J＝7.5Hz,1H),6.41(d,J＝12.7Hz,2H),5.53(s,1H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.9,152.9,139.4,138.7,136.9,130.7,130.3,129.6,129.6,127.9,126.6,125.3,125.0,123.0,73.9, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₁₆H₁₄NO₃S) m/z 300.0689, found m/z 300.0685.

Example 19

Compound 2r characterization data: yellow oil, 19.4mg, 71% yield.¹H NMR(400MHz,CDCl₃)δ7.29(m,J＝8.5,8.1,1.7Hz,1H),7.24–7.08(m,2H),6.90(d,J＝7.5Hz,1H),6.43(s,1H),6.25(s,1H),5.45(s,1H),3.82(s,3H),2.55–2.18(m,2H),1.59(m,J＝15.5,7.8,4.6Hz,2H),1.36(m,J＝14.6,9.4,5.4Hz,2H),0.90(t,J＝7.3Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.9,162.6,139.0,138.7,129.6,129.7,126.4,125.0,124.4,122.2,73.2,52.3,35.0,28.3,22.7, 13.8. HRMS accurate mass calculation [ M + H]⁺(C₁₆H₂₀NO₃) m/z 273.1365, found m/z 274.1433.

Example 20

Compound 2s characterization data: yellow oil, 25.6mg, 83% yield.¹H NMR(400MHz,CDCl₃)δ8.07(m,J＝8.3,1.3Hz,2H),7.50–7.44(m,1H),7.44–7.38(m,2H),7.25(d,J＝10.9Hz,1H),7.18–7.10(m,1H),6.83(s,1H),6.41(d,J＝7.7Hz,2H),5.53(s,1H),3.84(s,3H),2.34(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.1,155.6,139.0,137.1,136.7,132.8,131.5,130.2,129.6,128.4,128.0,125.7,125.1,122.9,73.6,52.4, 21.4. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₃) m/z 308.1281, found m/z 308.1277.

Example 21

Compound 2t characterization data: yellow oil, 28.0mg, 90% yield.¹H NMR(400MHz,CDCl₃)δ8.20–7.97(m,2H),7.51(m,J＝8.3,6.3Hz,1H),7.44(t,J＝7.5Hz,2H),7.08(m,J＝9.6,2.3Hz,1H),7.01(m,J＝8.4,5.9Hz,1H),6.91(m,J＝8.4,2.5Hz,1H),6.43(s,2H),5.55(s,1H),3.84(s,3H)。¹³C NMR(101MHz,CDCl₃)δ165.8,163.4(J_CF＝246.4Hz),157.1,141.3(J_CF＝9.1Hz),138.7,132.1,132.0,129.5,128.5,128.3,126.5(J_CF＝10.1Hz),118.8(J_CF＝3.0Hz),113.5(J_CF＝22.2Hz),112.2(J_CF23.2Hz),73.6, 52.5. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅FNO₃) m/z 311.0958, found m/z 312.1023.

Example 22

Characterization data for compound 2 u: yellow oil, 31.1mg,95% yield.¹H NMR(400MHz,CDCl₃)δ8.18–8.00(m,2H),7.57–7.48(m,1H),7.47–7.40(m,2H),7.35(d,J＝2.2Hz,1H),7.21–7.13(m,1H),6.98(d,J＝8.6Hz,1H),6.43(d,J＝6.4Hz,2H),5.57(s,1H),3.83(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.8,157.2,140.8,138.7,135.0,132.2,132.0,129.5,128.5,128.3,126.6,126.3,125.3,121.5,73.6, 52.5. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅ClNO₃) m/z 328.0735, found m/z 328.0730.

Example 23

Compound 2v characterization data: yellow oil, 34.7mg, 93% yield.¹H NMR(400MHz,CDCl₃)δ8.15–8.03(m,2H),7.57–7.48(m,2H),7.47–7.39(m,2H),7.32(m,J＝8.1,2.0Hz,1H),6.92(d,J＝8.1Hz,1H),6.42(d,J＝13.4Hz,2H),5.58(s,1H),3.83(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.7,157.2,141.0,138.6,132.2,132.0,129.5,129.5,128.5,128.3,128.3,126.6,122.9,122.0,73.6, 52.5. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₅BrNO₃) m/z 372.0230, found m/z 372.0231.

Example 24

Compound 2w characterization data: yellow oil, 24.9mg, 81% yield.¹H NMR(400MHz,CDCl₃)δ8.15–7.93(m,2H),7.50–7.44(m,1H),7.44–7.38(m,2H),7.25(d,J＝10.9Hz,2H),7.15(m,J＝8.0,2.1Hz,1H),6.83(s,1H),6.41(d,J＝7.7Hz,2H),5.53(s,1H),3.84(s,3H),2.34(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 166.1,156.3,139.5,139.3,139.1,132.7,131.56,129.3,128.4,128.1,127.5,125.9,125.1,120.2,73.7,52.3, 21.4. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₈NO₃) m/z 308.1281, found m/z 308.1277.

Example 25

Compound 2x characterization data: yellow oil, 27.8mg, 86% yield.¹H NMR(400MHz,CDCl₃)δ8.13–8.05(m,2H),7.39–7.29(m,2H),7.20(m,J＝7.1,1.8Hz,1H),7.14–7.06(m,2H),7.05–7.00(m,1H),6.43(d,J＝5.6Hz,2H),5.51(s,1H),4.29(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H)。¹³C NMR(101MHz,CDCl₃)δ165.5,165.1(J_CF＝252.9Hz),155.4,139.4,139.2,130.4(J_CF＝9.0Hz),129.6,129.4,128.8(J_CF＝3.1Hz),126.8,125.2,125.2,123.0,115.5(J_CF22.0Hz),73.9,61.4, 14.3. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₇FNO₃) m/z 326.1187, found m/z 326.1181.

Example 26

Compound 2y characterization data: yellow oil, 29.8mg, 87% yield.¹H NMR(400MHz,CDCl₃)δ8.08–7.99(m,2H),7.41–7.36(m,2H),7.36–7.30(m,2H),7.20(m,J＝7.2,1.9Hz,1H),7.02(m,J＝7.6,1.3Hz,1H),6.43(d,J＝6.6Hz,2H),5.51(s,1H),4.28(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.4,155.3,139.3,139.2,137.8,131.2,129.6,129.5,129.4,128.7,126.9,125.3,125.3,123.1,74.0,61.4, 14.3. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₇ClNO₃) m/z 342.0891, found m/z 342.0887.

Example 27

Compound 2z characterization data: yellow oil, 35.4mg, 92% yield.¹H NMR(400MHz,CDCl₃)δ7.99–7.93(m,2H),7.58–7.52(m,2H),7.39–7.29(m,2H),7.20(m,J＝7.1,2.0Hz,1H),7.05–6.98(m,1H),6.43(d,J＝6.1Hz,2H),5.50(s,1H),4.28(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.4,155.4,139.2,139.2,131.7,131.6,129.6,129.6,129.4,127.0,126.4,125.3,125.3,123.0,74.0,61.4, 14.3. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₇ClNO₃) m/z 386.0386, found m/z 386.0380.

Example 28

Chiral dihydroquinazolinones are structural units widely existing in bioactive molecules and natural products, and many asymmetric catalytic synthesis methods for synthesizing chiral dihydroquinazolinones exist at present, but all of the methods need to use a metal/ligand catalytic system. The invention successfully constructs the chiral 3, 4-dihydroquinazolin-2-one compound through the [4+2] cyclization reaction of a novel 4H-benzo [ d ] [1,3] oxazine compound and isocyanate under the organic catalysis condition, and the reaction has good yield and enantioselectivity.

Reaction of compound 2a with 4-methoxyphenyl isocyanate 4a in the presence of chiral phosphine P2 gave 3, 4-dihydroquinazolin-2-one 5aa in 43% yield and 39% ee. By screening the chiral phosphine organic catalyst, the yield and enantioselectivity are improved, and the yield of 44% ee and 85% ee can be obtained by adopting the optimal chiral phosphine P5 for reaction. Further optimization of the reaction conditions found that: in the usual organic solvents, CH₂Cl₂Is the best solvent; the effect of temperature on the reaction is observed to find that: when the reaction was carried out at-5 ℃ the product 5aa was obtained in 50% yield, 89% ee. By changing the proportion of reactants and the dosage of a catalyst, the yield can be improved to 61% under the condition of not influencing enantioselectivity; by screening the reaction concentration, the yield can be improved to 75%; adding Na₂SO₄With the additive, the results are not significantly improved. The final optimal reaction conditions are as follows: 4-methoxyphenyl isocyanate 4a (0.075mmol),4H-benzo [ d ]][1,3]Oxazine derivative 2a (0.05mmol), P5(20 mol%) CH₂Cl₂(3.0mL) the solution was stirred at-5 ℃ for 24 hours; the 3, 4-dihydroquinazolin-2 one was successfully obtained in 5aa, 75% yield, 90% ee.

TABLE 2

Reaction conditions are as follows: a mixture of 2a (0.05mmol), 4a (0.06mmol) and catalyst (10 mol%) was stirred in the indicated solvent (1.0mL) under Ar at the indicated temperature for 24 h. [ d ]]4a(0.075mmol)，P5(20mol％)；[e]CH₂Cl₂(2.0mL)；[f]CH₂Cl₂(3.0mL)；[g]CH₂Cl₂(4.0mL)；[h]Na₂SO₄(20mg)。

Compound 5aa characterization data:

light viscous oil, 16.6mg, 75% yield.¹H NMR(400Hz,CDCl₃):δ7.93–7.82(m,2H),7.53(ddd,J＝12.5,6.8,4.2Hz,2H),7.43(dd,J＝10.5,4.6Hz,2H),7.37–7.27(m,2H),7.20–7.12(m,3H),6.93–6.76(m,2H),6.37(s,1H),5.81(s,1H),5.77(d,J＝0.7Hz,1H),3.77(s,3H),3.73(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.7,165.9,158.4,152.2,139.4,136.2,135.7,133.7,132.7,129.2,128.9,128.6,127.8,126.7,126.7,124.5,123.3,118.6,114.3,63.5,55.5, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₃N₂O₅) m/z 443.1601, found m/z 433.1606. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝13.909min,t_R(major)＝20.523min,90％ee.[α]²⁰ _D＝-75.0(c＝1.00,CH₂Cl₂)。

To a solution of compound 2(0.05mmol,1.0 equiv.), aryl isocyanate 4(0.075mmol,1.5 equiv.) in DCM (1.5mL) under Ar protection was added a solution of catalyst P5(20 mol%) in DCM (1.5 mL). The mixture was stirred at-5 ℃ for 24 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) to give product 5.

The application range of the asymmetric reaction catalyzed by the organic phosphine is wide, the benzoxazine compound in the previous embodiment can be reacted to obtain the chiral 3, 4-dihydroquinazolin-2-one derivative 5 (embodiment 29-50), and the yield and the enantioselectivity are high. The benzoxazine with different ester groups and 4-methoxyphenyl isocyanate 4a smoothly react to obtain a 3, 4-dihydroquinazolin-2-one compound, wherein the yield is 74-80%, and 86-90% ee; aromatic R with different electron withdrawing groups (F, Cl, Br) and electron donating groups (Me, MeO)³Obtaining a product with the yield of 71-78% and the ee of 89-91%, and obtaining a product with benzoxazine with aliphatic groups with the yield of 61% and the ee of 84%; different substituents R²Can also be incorporated into the aromatic ring of benzoxazines in yields of 63-81% and ee of 90-92%. The isocyanate with different substituents (F, Cl, Br and Me) can obtain a product with 73-81% of yield and 75-89% of ee no matter how the electronic property and the position of the isocyanate are changed; the reaction of 2v benzoxazine with 4g isocyanate gave 5vg of 3, 4-dihydroquinazolin-2-one in 80% yield and 83% ee.

Example 29

Pale yellow oil, 16.8mg, 74% yield.¹H NMR(400MHz,CDCl₃)δ7.97–7.78(m,2H),7.61–7.48(m,2H),7.44(t,J＝7.5Hz,2H),7.38–7.28(m,2H),7.22–7.11(m,3H),6.92–6.77(m,2H),6.37(s,1H),5.83(s,1H),5.74(d,J＝0.6Hz,1H),4.35–4.05(m,2H),3.77(s,3H),1.24(t,J＝7.1Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.5,158.4,152.3,139.7,136.2,135.7,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.4,124.5,123.6,118.8,114.3,63.3,61.4,55.5, 14.1. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₅) m/z 457.1758, found m/z 457.1759. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝12.23min,t_R(major)＝17.761min,87％ee.[α]²⁰ _D＝-100.74(c＝1.00,CH₂Cl₂)。

Example 30

Pale yellow oil, 19.1mg, 79% yield.¹H NMR(400MHz,CDCl₃)δ7.86(dd,J＝5.2,3.3Hz,2H),7.53(ddd,J＝8.0,6.7,4.7Hz,2H),7.43(dd,J＝10.4,4.7Hz,2H),7.32(dt,J＝9.5,4.1Hz,2H),7.22–7.09(m,3H),6.90–6.79(m,2H),6.35(s,1H),5.83(s,1H),5.74(d,J＝0.8Hz,1H),4.25–4.04(m,2H),3.77(s,3H),1.65–1.49(m,2H),1.34(dq,J＝14.6,7.3Hz,2H),0.93(t,J＝7.4Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.6,158.4,152.3,139.7,136.2,135.8,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.3,124.5,123.6,118.8,114.3,65.3,63.3,55.5,30.5,19.2, 13.8. HRMS accurate mass calculation [ M + H]⁺(C₂₉H₂₉N₂O₅) m/z 485.2071, found m/z 485.2074. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝11.729min,t_R(major)＝17.575min,86％ee.[α]²⁰ _D＝-108.44(c＝1.00,CH₂Cl₂)。

Example 31

Pale yellow oil, 19.3mg, 80% yield.¹H NMR(400MHz,CDCl₃)δ7.92–7.81(m,2H),7.61–7.48(m,2H),7.43(dd,J＝10.5,4.6Hz,2H),7.38–7.27(m,2H),7.22–7.10(m,3H),6.91–6.77(m,2H),6.36(s,1H),5.84(s,1H),5.77(d,J＝0.7Hz,1H),3.94(qd,J＝10.6,6.7Hz,2H),3.77(s,3H),1.93(dp,J＝13.4,6.7Hz,1H),0.92(dd,J＝6.7,3.7Hz,6H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.5,158.4,152.3,139.7,136.1,135.7,133.8,132.6,129.1,128.9,128.5,127.8,126.7,126.2,124.5,123.6,118.8,114.3,77.4,71.4,63, 55.5,27.7,19.1, 19.1. HRMS accurate mass calculation [ M + H]⁺(C₂₉H₂₉N₂O₅) m/z 485.2071, found m/z 485.2076. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝11.377min,t_R(major)＝17min,86％ee.[α]²⁰ _D＝-116.74(c＝1.00,CH₂Cl₂)。

Example 32

Pale yellow oil, 19.9mg, 77% yield.¹H NMR(400MHz,CDCl₃)δ7.92–7.82(m,2H),7.64–7.48(m,2H),7.47–7.27(m,9H),7.21–7.06(m,3H),6.89–6.75(m,2H),6.40(s,1H),5.84(s,1H),5.77(d,J＝0.8Hz,1H),5.25(d,J＝12.2Hz,1H),5.12(d,J＝12.2Hz,1H),3.76(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.3,158.4,152.2,139.5,136.2,135.7,135.4,133.7,132.6,129.1,128.9,128.7,128.5,128.4,127.8,126.9,126.7,124.5,123.4,118.7,114.3,67.1,63.5, 55.5. HRMS accurate mass calculation [ M + H]⁺(C₃₂H₂₇N₂O₅) m/z 519.1914, found m/z 519.1920. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝14.667min,t_R(major)＝22.623min,86％ee.[α]²⁰ _D＝-103.70(c＝1.00,CH₂Cl₂)。

Example 33

Light yellow oil, 17.9mg, 78% yield.¹H NMR(400MHz,CDCl₃)δ8.00–7.85(m,2H),7.43(dd,J＝5.9,3.0Hz,1H),7.34–7.27(m,2H),7.22–7.02(m,5H),6.92–6.78(m,2H),6.33(s,1H),5.78(s,1H),5.72(d,J＝0.7Hz,1H),3.77(s,3H),3.73(s,3H)。¹³C NMR(101MHz,CDCl₃)δ170.8,165.8,165.6(J_CF＝262.6Hz),158.5,152.1,139.6,136.1,133.6,132.0(J_CF＝10.1Hz),129.0,128.0,126.8(J_CF＝10.1Hz),124.5,122.98,118.2,115.8(J_CF20.2Hz),114.4,63.8,55.5, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂FN₂O₅) m/z 461.1507, found m/z 461.1509. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝13.506min,t_R(major)＝17.901min,90％ee.[α]²⁰ _D＝-105.48(c＝1.00,CH₂Cl₂)。

Example 34

Pale yellow oil, 16.8mg, 71% yield.¹H NMR(400MHz,CDCl₃)δ7.86–7.77(m,2H),7.55(d,J＝8.2Hz,1H),7.46–7.38(m,2H),7.36–7.28(m,2H),7.21–7.09(m,3H),6.89–6.81(m,2H),6.33(s,1H),5.77(s,1H),5.69(d,J＝0.8Hz,1H),3.77(s,3H),3.72(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 170.9,165.8,158.5,152.2,139.5,138.9,136.0,134.4,133.6,130.5,129.0,128.9,127.9,126.8,126.7,124.7,123.4,118.8,114.4,63.8,55.5, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂ClN₂O₅) m/z 477.1212, found m/z 477.1216. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝15.325min,t_R(major)＝20.078min,90％ee.[α]²⁰ _D＝-81.77(c＝1.00,CH₂Cl₂)。

Example 35

Light yellow oil, 18.9mg, 73% yield.¹H NMR(400MHz,CDCl₃)δ7.77–7.69(m,2H),7.58(t,J＝5.4Hz,3H),7.37–7.29(m,2H),7.22–7.08(m,3H),6.92–6.79(m,2H),6.32(s,1H),5.77(s,1H),5.68(d,J＝0.8Hz,1H),3.77(s,3H),3.72(s,3H).¹³C NMR(101MHz,CDCl₃) δ 171.0,165.8,158.5,152.2,139.4,136.0,134.9,133.6,131.9,130.6,129.0,127.9,127.5,126.8,126.7,124.8,123.5,119.0,114.5, 63.8655.6, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂BrN₂O₅) m/z 521.0707, found m/z 521.0710. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝16.685min,t_R(major)＝21.538min,91％ee.[α]²⁰ _D＝-94.81(c＝1.00,CH₂Cl₂)。

Example 36

Light yellow oil, 17.1mg, 75% yield.¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝8.2Hz,2H),7.39(d,J＝7.8Hz,1H),7.35–7.27(m,2H),7.25(d,J＝8.1Hz,2H),7.21–7.08(m,3H),6.90–6.80(m,2H),6.37(s,1H),5.82(s,1H),5.79(s,1H),3.78(s,3H),3.74(s,3H),2.40(s,3H)。¹³C NMR(101MHz,CDCl₃)δ171.7,165.9,158.3,152.2,143.9,139.6,136.3,133.8,132.7,129.7,129.4,128.9,127.9,126.8,126.7,124.2,122.8,118.0,114.3,63.4,55.5,52.3,21.8. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₅) m/z 457.1758, found m/z 457.1760. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝19.757min,t_R(major)＝25.389min,89％ee.[α]²⁰ _D＝-67.55(c＝1.00,CH₂Cl₂)。

Example 37

Light yellow oil, 17.7mg, 75% yield.¹H NMR(400MHz,CDCl₃)δ8.02–7.92(m,2H),7.29(dd,J＝7.6,1.1Hz,1H),7.25–7.12(m,4H),7.08(td,J＝7.5,1.1Hz,1H),6.96–6.89(m,2H),6.89–6.81(m,2H),6.35(s,1H),5.82(s,2H),3.85(s,3H),3.77(s,3H),3.74(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.1,165.8,164.1,158.3,152.0,139.8,136.3,133.7,132.5,128.9,128.0,127.4,126.9,126.8,123.7,121.9,116.9,114.3,114.1,63.5,55.6,55.5, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₆) m/z 473.1707, found m/z 473.1713. HPLC conditions are Daicel Chiralpak IB column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min,. lambda.254 nm, retention time t_R(minor)＝18.373min,t_R(major)＝25.589min,90％ee.[α]²⁰ _D＝-67.55(c＝1.00,CH₂Cl₂)。

Example 38

Pale yellow oil, 17.2mg, 73% yield.¹H NMR(400MHz,CDCl₃)δ7.51(d,J＝8.1Hz,1H),7.48–7.39(m,2H),7.38–7.28(m,3H),7.21–7.11(m,3H),7.11–7.03(m,1H),6.90–6.80(m,2H),6.37(s,1H),5.80(s,1H),5.77(s,1H),3.83(s,3H),3.77(s,3H),3.72(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.8,159.7,158.4,152.2,139.4,137.0,136.2,133.7,129.6,128.9,127.8,126.9,126.7,124.5,123.1,121.6,119.4,118.5,114.3,113.6,63.6,55.5, 52.3. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₆) m/z 473.1707, found m/z 473.1710. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝17.166min,t_R(major)＝29.453min,90％ee.[α]²⁰ _D＝-66.96(c＝1.00,CH₂Cl₂)。

Example 39

Pale yellow oil, 13.0mg, 61% yield.¹H NMR(400MHz,CDCl₃)δ7.80(d,J＝8.2Hz,1H),7.44(d,J＝7.4Hz,1H),7.38(dd,J＝11.3,4.4Hz,1H),7.25–7.15(m,3H),6.90(d,J＝8.9Hz,2H),6.34(s,1H),5.82(d,J＝1.0Hz,1H),5.62(s,1H),3.80(s,3H),3.70(s,3H),3.15(ddd,J＝16.4,8.7,5.8Hz,1H),2.76–2.63(m,1H),1.81–1.65(m,2H),1.37(dt,J＝14.3,7.1Hz,2H),0.93(t,J＝7.3Hz,3H)。¹³C NMR(101MHz,CDCl₃) δ 173.09,165.70,158.61,154.05,139.49,138.40,135.06,134.39,128.22,128.04,126.86,126.77,125.91,124.92,124.12,114.58,63.27,55.65,52.35,36.99,27.42,22.52, 14.07. HRMS accurate mass calculation [ M + H]⁺(C₂₄H₂₇N₂O₅) m/z 423.1914, found m/z 423.1909. HPLC conditions are Daicel Chiralpak IC-3 column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝9.841min,t_R(major)＝17.015min,84％ee.[α]²⁰ _D＝-56.16(c＝1.00,CH₂Cl₂)。

Example 40

Light yellow oil, 18.0mg, 79% yield.¹H NMR(400MHz,CDCl₃)δ7.87–7.75(m,2H),7.55–7.46(m,2H),7.42(t,J＝7.5Hz,2H),7.18–7.06(m,4H),6.90–6.77(m,2H),6.36(s,1H),5.75(s,1H),5.73(s,1H),3.77(s,3H),3.72(s,3H),2.34(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,166.0,158.4,152.4,139.5,136.0,134.5,133.9,133.8,132.4,129.5,129.0,128.5,127.9,127.0,126.8,123.8,119.2,114.3,63.5,55.5,52.3, 20.9. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₅) m/z 457.1758, found m/z 457.1759. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝13.958min,t_R(major)＝20.84min,91％ee.[α]²⁰ _D＝-88.29(c＝1.00,CH₂Cl₂)。

EXAMPLE 41

Pale yellow oil, 14.5mg, 63% yield.¹H NMR(400MHz,CDCl₃)δ7.89(dd,J＝5.2,3.4Hz,2H),7.58–7.51(m,1H),7.45(dd,J＝10.5,4.7Hz,2H),7.30(ddd,J＝14.6,9.6,4.2Hz,2H),7.21–7.07(m,2H),6.95–6.69(m,3H),6.37(s,1H),5.77(d,J＝1.4Hz,2H),3.77(s,3H),3.74(s,3H)。¹³C NMR(101MHz,CDCl₃)δ171.8,165.7,162.6(J_CF＝242.4Hz),158.5,151.9,139.4,137.3(J_CF＝10.1Hz),135.5,133.5,133.0,129.2,128.7,128.1(J_CF＝10.1Hz),127.8,126.8,118.6(J_CF＝3.0Hz),114.4,111.2(J_CF＝30.3Hz),105.9(J_CF20.2Hz),63.2,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂FN₂O₅) m/z 461.1507, found m/z 461.1509. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝10.453min,t_R(major)＝14.976min,92％ee.[α]²⁰ _D＝-81.77(c＝1.00,CH₂Cl₂)。

Example 42

Light yellow oil, 18.5mg, 78% yield.¹H NMR(400MHz,CDCl₃)δ7.97–7.84(m,2H),7.55(dd,J＝12.5,4.7Hz,2H),7.45(t,J＝7.6Hz,2H),7.24(s,1H),7.20–7.05(m,3H),6.93–6.76(m,2H),6.37(s,1H),5.78(s,1H),5.76(s,1H),3.76(s,3H),3.74(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.8,165.6,158.5,151.8,139.2,137.1,135.4,134.8,133.4,133.1,129.3,128.7,127.9,127.8,127.1,124.4,121.2,118.1,114.4,63.3,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂ClN₂O₅) m/z 477.1212, found m/z 477.1215. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝11.462min,t_R(major)＝16.349min,92％ee.[α]²⁰ _D＝-58.66(c＝1.00,CH₂Cl₂)。

Example 43

Light yellow oil, 21.0mg, 81% yield.¹H NMR(400MHz,CDCl₃)δ7.95–7.83(m,2H),7.68(d,J＝1.8Hz,1H),7.61–7.52(m,1H),7.45(dd,J＝10.6,4.7Hz,2H),7.27(dd,J＝8.0,1.6Hz,1H),7.18(dd,J＝8.7,5.3Hz,1H),7.16–7.09(m,2H),6.91–6.76(m,2H),6.38(s,1H),5.78(d,J＝0.8Hz,1H),5.74(s,1H),3.76(s,3H),3.74(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.8,165.6,158.5,151.8,139.2,137.2,135.4,133.3,133.1,129.3,128.7,128.2,127.8,127.3,127.1,122.6,121.7,120.9,114.4,63.4,55.5, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₂BrN₂O₅) m/z 521.0707, found m/z 521.0712. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝12.087min,t_R(major)＝17.193min,92％ee.[α]²⁰ _D＝-101.92(c＝1.00,CH₂Cl₂)。

Example 44

Pale yellow oil, 16.4mg, 72% yield.¹H NMR(400MHz,CDCl₃)δ7.98–7.85(m,2H),7.53(dd,J＝10.6,4.2Hz,1H),7.44(t,J＝7.6Hz,2H),7.29(s,1H),7.20(d,J＝7.8Hz,1H),7.18–7.12(m,2H),6.96(d,J＝7.8Hz,1H),6.90–6.77(m,2H),6.34(s,1H),5.77(s,1H),5.76(s,1H),3.76(s,3H),3.73(s,3H),2.33(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 172.0,165.9,158.3,152.3,139.7,139.1,136.0,135.8,133.8,132.7,129.2,128.6,127.9,126.6,126.5,125.2,120.2,118.8,114.3,63.4,55.5,52.2, 21.6. HRMS accurate mass calculation [ M + H]⁺(C₂₇H₂₅N₂O₅) m/z 457.1758, found m/z 457.1760. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝13.245min,t_R(major)＝17.217min,90％ee.[α]²⁰ _D＝-74.66(c＝1.00,CH₂Cl₂)。

Example 45

The reaction temperature was 0 ℃.

Pale yellow oil, 18.0mg, 84% yield.¹H NMR(400MHz,CDCl₃)δ7.94–7.84(m,2H),7.59–7.51(m,1H),7.45(td,J＝7.6,2.9Hz,3H),7.37–7.28(m,2H),7.26–7.20(m,2H),7.16(td,J＝7.5,1.0Hz,1H),7.08–6.96(m,2H),6.38(s,1H),5.83(s,1H),5.76(d,J＝0.9Hz,1H),3.74(s,3H)。¹³C NMR(101MHz,CDCl₃)δ171.7,165.8,161.2(J_CF＝242.4Hz),152.1,139.3,136.9,136.8,136.1,135.5,133.0,129.3,129.1,128.7,128.3(J_CF＝10.1Hz),126.8(J_CF＝10.1Hz),124.6,122.9,118.4,116.0(J_CF20.2Hz),63.3, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₅H₂₀FN₂O₄) m/z 431.1402, found m/z 431.1406. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝7.9min,t_R(major)＝11.496min,89％ee.[α]²⁰ _D＝-83.55(c＝1.00,CH₂Cl₂)。

Example 46

The reaction temperature was room temperature.

Pale yellow oil, 16.9mg, 76% yield.¹H NMR(400MHz,CDCl₃)δ7.92–7.84(m,2H),7.60–7.52(m,1H),7.50–7.40(m,3H),7.32(ddt,J＝9.3,4.7,1.9Hz,4H),7.24–7.12(m,3H),6.39(s,1H),5.84(s,1H),5.78(d,J＝1.1Hz,1H),3.75(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.6,165.7,152.0,139.4,139.2,136.0,135.4,133.1,132.5,129.4,129.2,129.1,128.7,127.6,126.9,126.8,124.6,122.8,118.4,63.0, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₅H₂₀ClN₂O₄) m/z 447.1106, found m/z 447.1110. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝9.257min,t_R(major)＝13.839min,75％ee.[α]²⁰ _D＝-57.48(c＝1.00,CH₂Cl₂)。

Example 47

The reaction temperature was room temperature.

Pale yellow oil, 17.8mg, 73% yield.¹H NMR(400MHz,CDCl₃)δ7.88(dd,J＝5.2,3.3Hz,2H),7.60–7.51(m,1H),7.51–7.39(m,5H),7.39–7.28(m,2H),7.17(ddd,J＝6.8,4.1,1.6Hz,3H),6.39(s,1H),5.85(s,1H),5.78(d,J＝1.0Hz,1H),3.75(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.5,165.7,151.9,139.9,139.1,135.9,135.3,133.11,132.1,129.3,129.1,128.7,127.8,126.8,126.7,124.6,122.7,120.4,118.3,62.9, 52.4. HRMS accurate mass calculation [ M + H]⁺(C₂₅H₂₀BrN₂O₄) m/z 491.0601, found m/z 491.0605. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝9.925min,t_R(major)＝14.64min,78％ee.[α]²⁰ _D＝-56.88(c＝1.00,CH₂Cl₂)。

Example 48

Pale yellow oil, 17.4mg, 82% yield.¹H NMR(400MHz,CDCl₃)δ7.91–7.79(m,2H),7.55–7.49(m,2H),7.43(dd,J＝10.4,4.7Hz,2H),7.38–7.28(m,2H),7.22–7.10(m,5H),6.38(s,1H),5.84(s,1H),5.79(d,J＝1.1Hz,1H),3.73(s,3H),2.31(s,3H).¹³C NMR(101MHz,CDCl₃) δ 171.7,165.9,152.2,139.4,138.4,136.9,136.2,135.7,132.7,129.7,129.2,128.9,128.6,126.8,126.5,126.1,124.5,123.4,118.8,63.2,52.3, 21.1. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₃N₂O₄) m/z 427.1652, found m/z 427.1656. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝10.895min,t_R(major)＝17.625min,89％ee.[α]²⁰ _D＝-82.96(c＝1.00,CH₂Cl₂)。

Example 49

Pale yellow oil, 17.2mg, 81% yield.¹H NMR(400MHz,CDCl₃)δ7.88–7.81(m,2H),7.53(ddd,J＝8.3,4.8,2.1Hz,2H),7.43(dd,J＝10.4,4.7Hz,2H),7.37(d,J＝7.6Hz,1H),7.34–7.27(m,1H),7.24–7.12(m,2H),7.05(dd,J＝9.2,7.8Hz,3H),6.39(s,1H),5.85(s,1H),5.81(d,J＝1.1Hz,1H),3.73(s,3H),2.31(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.7,165.9,152.3,140.9,139.4,139.1,136.1,135.7,132.7,129.2,129.0,128.9,128.6,127.9,126.9,126.4,124.6,123.4,123.1,118.8,63.0,52.3, 21.5. HRMS accurate mass calculation [ M + H]⁺(C₂₆H₂₃N₂O₄) m/z 427.1652, found m/z 427.1654. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝8.287min,t_R(major)＝14.593min,88％ee.[α]²⁰ _D＝-84.14(c＝1.00,CH₂Cl₂)。

Example 50

Pale yellow solid, mp 73.1-74.7 ℃,34.6mg, 80% yield.¹H NMR(400MHz,CDCl₃)δ7.94–7.86(m,2H),7.69–7.52(m,4H),7.46(t,J＝7.7Hz,2H),7.28(dd,J＝8.2,1.7Hz,1H),7.22(d,J＝8.2Hz,1H),7.00(dd,J＝9.2,2.3Hz,2H),6.39(s,1H),5.79(d,J＝0.7Hz,1H),5.77(s,1H)。¹³C NMR(101MHz,CDCl₃) δ 171.58,165.51,151.56,140.34,138.80,138.32,136.98,135.02,133.54,129.48,128.86,128.35,128.05,127.51,127.09,122.90,121.20,120.77,91.99,62.68, 52.55. HRMS accurate mass calculation [ M + H]⁺(C₂₅H₁₉BrIN₂O₄) m/z 616.9567, found m/z 616.9573. HPLC condition, Daicel ChiralpakIF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝8.989min,t_R(major)＝13.171min,83％ee.[α]²⁰ _D＝-93.33(c＝1.00,CH₂Cl₂)。

The absolute configuration of compound 5vg was confirmed by X-ray crystallography as S.

Example 51

The reaction was scaled up to 1.0mmol of starting material, and 1.0mmol of 4H-benzo [ d ] [1,3] oxazine 2u was reacted with 1.5mmol of 4-methoxyphenyl isocyanate 4a at room temperature to give 3, 4-dihydroquinazolin-2 one 5ua in 63% yield (0.3g) with an ee of 92%.

Example 52

The subsequent transformation of 3, 4-dihydroquinazolin-2-one was allowed and the compound 5ua was reduced with diisobutylaluminum hydride (DIBAL-H) at-70 ℃ to give the alcohol 6ua in 64% yield without loss of enantioselectivity.

DIBAL-H (1mL, 1M in THF) was added dropwise to a solution of 5ua (0.05mmol,1.0 eq.) in 1mL dry DCM under Ar protection at-70 ℃. The mixture was stirred for 30 min, then quenched with 1M dilute hydrochloric acid (1mL), and the resulting mixture was extracted with DCM (10 mL. times.3). The combined organic phases were washed successively with water (10mL) and brine (10mL) and then Na₂SO₄Drying, filtering, and concentrating under reduced pressureAnd (4) shrinking. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give the product 6ua (11.0mg, 64% yield, 92% ee).

Product characterization data: pale yellow oil, 11.0mg, 64% yield.¹H NMR(400MHz,CDCl₃)δ8.55(s,1H),7.25(d,J＝8.4Hz,3H),7.00(d,J＝8.1Hz,1H),6.89(t,J＝9.7Hz,3H),6.73(s,1H),5.32(s,1H),5.16(s,1H),5.07(s,1H),4.17(d,J＝14.2Hz,1H),4.00(d,J＝14.2Hz,1H),3.78(s,3H),2.25(s,1H)。¹³C NMR(101MHz,CDCl₃) δ 158.37,153.92,147.03,137.44,134.36,133.84,128.33,127.34,122.35,118.44,114.47,113.72,66.09,62.00, 55.56. HRMS accurate mass calculation [ M + H]⁺(C₁₈H₁₈ClN₂O₃) m/z 345.1000, found m/z 345.1003. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time t_R(major)＝10.481min,t_R(minor)＝12.466min,92％ee.[α]²⁰ _D＝-48.25(c＝1.00,CH₂Cl₂)。

Example 53

3, 4-dihydroquinazolin-2-one 5aa and Smi₂And (3) reacting, removing benzoyl to obtain 3, 4-dihydroquinazolin-2-one 7aa with the yield of 85% and the ee of 86%.

To a solution of 5aa (0.05mmol,1.0 equiv.) in THF (1mL) at room temperature was added SmI₂(3mL, 0.1M in THF, 6.0 equiv.). The mixture was stirred for 30 min and then concentrated to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) to give the product 7aa (14.3mg, 85% yield, 86% ee).

Product characterization data: pale yellow solid, mp 90.1-93.7 ℃,14.3mg, 85% yield.¹H NMR(400MHz,CDCl₃)δ8.19(s,1H),7.32–7.26(m,3H),7.22(d,J＝7.7Hz,1H),7.04–6.90(m,3H),6.80(d,J＝7.9Hz,1H),6.34(s,1H),5.95(s,1H),5.83(s,1H),3.84(s,3H),3.75(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 165.94,158.24,154.24,139.78,136.05,134.08,128.81,128.08,126.44,126.14,122.38,120.03,114.44,63.12,55.57, 52.24. HRMS accurate mass calculation [ M + H]⁺(C₁₉H₁₉N₂O₄) m/z 339.1339, found m/z 339.1342. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝22.628min,t_R(major)＝28.374min,86％ee.[α]²⁰ _D＝-45.0(c＝1.00,CH₂Cl₂)。

Example 54

3, 4-dihydroquinazolin-2-one 5aa and N-hydroxybenzoyl chloride were subjected to a [3+2] cyclization reaction to give the product 8aa in 83% yield with an ee of 86%.

To a solution of N-hydroxybenzoyl chloride (0.1mmol, 2.0 equiv.) in DCM (1mL) at room temperature was added Et₃N (0.1mmol, 2.0 equiv.). After stirring for 10 min, 5aa (0.05mmol,1.0 eq) in 1mL DCM was added to the solution. The mixture was stirred for 1 hour and then concentrated to give the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1) to give the product 8aa (23.2mg, 83% yield, 86% ee).

Product characterization data: pale yellow oil, 23.2mg, 83% yield.¹H NMR(400MHz,CDCl₃)δ8.14–8.05(m,2H),7.73(d,J＝8.1Hz,1H),7.63–7.55(m,1H),7.54–7.46(m,4H),7.45–7.30(m,5H),7.24–7.14(m,3H),6.87–6.77(m,2H),5.67(s,1H),3.94(d,J＝17.5Hz,1H),3.76(s,3H),3.61(d,J＝17.5Hz,1H),3.44(s,3H)。¹³C NMR(101MHz,CDCl₃) δ 171.64,170.93,158.51,157.07,152.40,137.23,135.52,134.18,132.87,130.84,129.89,129.37,128.91,128.68,128.61,128.20,127.93,126.91,124.73,120.37,119.14,114.28,91.81,65.58,55.65,53.17, 39.90. HRMS accurate mass calculation [ M + H]⁺(C₃₃H₂₈N₃O₆) m/z 562.1973, practiceM/z 562.1978 was measured. HPLC conditions are Daicel Chiralpak IF-3 column, n-hexane/2-propanol 60/40, flow rate 1.0mL/min, lambda 254nm, retention time t_R(minor)＝17.63min,t_R(major)＝22.014min,86％ee.[α]²⁰ _D＝-60.12(c＝1.00,CH₂Cl₂)。

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A benzoxazine compound having the structure of formula i:

wherein R is¹Is alkyl or benzyl;

R²is hydrogen, alkyl or halogen;

2. The benzoxazine compound of claim 1, wherein R is¹Is (C1-C4) alkyl or benzyl.

3. The benzoxazine compound of claim 1, wherein R is²Hydrogen, (C1-C4) alkyl or halogen.

4. The benzoxazine compound of claim 1, wherein R is³Selected from phenyl, naphthyl, furyl, thienyl, alkyl substituted by halogen, alkyl or alkoxy.

5. The benzoxazine compound of claim 4, wherein R³Selected from the group consisting of fluorophenyl, chlorophenyl, bromophenyl, (C1-C4) alkyl-substituted phenyl, (C1-C4) alkoxy-substituted phenyl, naphthyl, furyl, thienyl, and (C1-C4) alkyl.

6. The benzoxazine compound of claim 5, wherein R is³Selected from naphthyl, furyl, thienyl and (C1-C4) alkyl.

7. Benzoxazine compound according to claim 1, characterized in that it is selected from the following compounds:

8. a method for synthesizing a benzoxazine compound according to any one of claims 1 to 7, comprising the steps of: in the presence of di-tert-butyl dicarbonate and a catalyst, the compound M1 reacts as follows:

wherein R is¹、R²、R³The method according to any one of claims 1 to 6; the catalyst is 1, 4-diazabicyclo [2.2.2]Octane or 4-dimethylaminopyridine.

9. The synthesis method according to claim 8, wherein the molar ratio of the compound M1 to di-tert-butyl dicarbonate is 1: (1-3); the dosage of the catalyst is more than 10 mol%; the reaction takes toluene, dichloromethane, chloroform, ethyl acetate or acetonitrile as solvents; the reaction temperature is above 20 ℃, and the reaction time is at least 24 h.

10. The use of a benzoxazine compound according to any one of claims 1 to 7 in the synthesis of a chiral quinazolinone, wherein a chiral phosphine catalyst is used, and compound i reacts with compound M2 to give the chiral quinazolinone compound:

wherein R is¹、R²、R³The method according to any one of claims 1 to 6; ar is selected from phenyl substituted by halogen, alkyl or alkoxy; the chiral phosphine catalyst is one of the following: