CN114736206B - Preparation method of alkane C (sp 3) -H functionalized started polycyclic quinazolinone derivative in aqueous phase - Google Patents

Preparation method of alkane C (sp 3) -H functionalized started polycyclic quinazolinone derivative in aqueous phase Download PDF

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CN114736206B
CN114736206B CN202210408539.5A CN202210408539A CN114736206B CN 114736206 B CN114736206 B CN 114736206B CN 202210408539 A CN202210408539 A CN 202210408539A CN 114736206 B CN114736206 B CN 114736206B
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alkane
quinazolinone
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CN114736206A (en
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易荣楠
陈瑶清
黄娟娟
唐钰强
胡润楷
肖大中
夏婵娟
卜芃
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Hunan Police Academy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Alkane C (sp) in aqueous phase 3 ) Process for the preparation of H-functionalized initiated polycyclic quinazolinone derivatives, which are C (sp 3 ) Functionalization of the H group to form an alkyl radical, followed by olefin-substituted quinazolinonesIs a novel method for effectively synthesizing polycyclic quinazolinone by free radical cyclization. Specifically, the raw materials of quinazolinone compound, alkane, phase transfer agent and oxidant are added into a solvent under the air atmosphere, and are stirred and reacted at a certain reaction temperature to generate the polycyclic quinazolinone derivative. The method has the advantages of wide application range of the reaction substrate, greenness and high efficiency, and is particularly suitable for industrial production.

Description

Alkane C (sp) in aqueous phase 3 ) Process for preparing H-functionalized initiated polycyclic quinazolinone derivatives
Technical Field
The invention belongs to the field of organic synthesis, and relates to alkane C (sp) 3 ) -H-functionalized initiated polycyclic quinazolinone derivatives.
Background
The synthesis of polycyclic quinazolinones is a core step in the preparation of natural products with pharmaceutical and biological activity. In addition, the molecular skeleton has antidepressant, antiasthmatic, antiinfectious and other medicinal properties. In general, there are various methods for synthesizing polycyclic quinazolinones, mainly comprising: 1) a reductive cyclization of a bisaryl azide, 2) a cyclization of an anthranilic acid, 3) an intramolecular photocatalytic reaction of a primary alcohol, and 4) a conversion of an N-cyanamide olefin. However, these methods have disadvantages such as complicated reaction conditions, complicated raw material preparation, and long reaction procedures. Recently, direct C-2 alkylation of olefin-substituted quinazolinones, independently of one another, has attracted attention as a series of polycyclic quinazolinones.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the high-efficiency, economic and environment-friendly alkane C (sp) 3 ) The method is a free radical cyclization reaction method, and a quinazolinone compound and an alkane compound are used as raw materials, so that a target product with high yield can be prepared in a water phase system.
In order to achieve the above purpose, the invention adopts the following technical scheme: alkane C (sp) in aqueous phase 3 ) The preparation method of the H-functionalized started polycyclic quinazolinone derivative comprises the steps of adding a quinazolinone compound of a raw material formula 1, alkane of a formula 2, a phase transfer agent and an oxidant into a solvent in air atmosphere, and stirring and reacting at a certain reaction temperature to generate the polycyclic quinazolinone derivative of the formula I, wherein the reaction formula is as follows:
wherein R in formula 1 1 Selected from hydrogen, C 1 -C 6 Alkyl, halogen or methoxy; n=1, 2 or 3; the unsaturated bond part is olefin or aromatic hydrocarbon; in 2Selected from C 5 -C 14 Is a hydrocarbon group.
Preferably, R in formula 1 1 Selected from hydrogen, chlorine, bromine, methyl or methoxy; the unsaturated bond moiety is an alkene or phenyl group. The alkane of formula 2 is selected from cyclopentane, cyclohexane, methylcyclohexane, cycloheptane, cyclooctane, cyclododecane, adamantane or n-hexane.
Preferably, the oxidizing agent is selected from one or more of dibenzoyl peroxide (BPO), di-tert-butyl peroxide (DTBP) or tert-butyl peroxide (TBHP), preferably di-tert-butyl peroxide. The phase transfer agent is selected from one or more of Sodium Dodecyl Sulfate (SDS), tetrabutylammonium iodide or 18-crown-6, preferably sodium dodecyl sulfonate. The solvent is water mixed with alkane.
Preferably, the reaction temperature is 85-95 ℃. At the beginning of the reaction, the dosage of the quinazolinone compound is 0.2mmol, the dosage of the oxidant is 0.4mmol, the dosage of the phase transfer agent is 0.04mmol, and the water/alkane is 1.5mL/0.5mL-1.9mL/0.1mL.
The invention relates to C (sp) 3 ) Novel methods for efficient synthesis of valuable polycyclic quinazolinones by H functionalization to alkyl radicals and subsequent free radical cyclization of olefin-substituted quinazolinones. The method prepares a series of target products with higher yield in a water-phase metal-free system, has the advantages of wide application range of reaction substrates, greenness and high efficiency, and is particularly suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, unless otherwise specified, may be obtained from commercial sources and/or prepared according to known methods.
Examples 1-10 are reaction condition optimization experiments.
Example 1
40.0mg (0.2 mmol) of the quinazolinone compound represented by formula 1a, 0.2mL of cyclohexane represented by formula 2a, 58.5mg (2.0 equiv) of di-tert-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added to a Schlenk reaction flask, and then the reaction flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (yield 87%), structural formula of the product was shown in formula I-1, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.28(d,J＝7.6Hz,1H),7.74-7.68(m,2H),7.46-7.42(m,1H),4.31-4.25(m,1H),4.03-3.96(m,1H),3.36-3.30(m,1H),2.50-2.42(m,1H),2.10-2.02(m,1H),1.93-1.85(m,2H),1.75-1.64(m,4H),1.47(t,J＝9.2Hz,2H),1.30-1.21(m,3H),1.09-0.98(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:162.4,161.1,149.3,134.0,127.0,126.3,126.1,120.7,44.7,41.4,39.7,35.5,34.4,32.0,26.7,26.5,26.4,26.2；HRMS m/z(ESI)calcd for C 18 H 23 N 2 O([M+H] + )283.1805,found 283.1801。
example 2
The oxidant was t-butyl peroxide (TBHP) instead of di-t-butyl peroxide (DTBP), and the other conditions were the same as in example 1 to give the desired product I-1 in a yield of 71%.
Example 3
The oxidant was Benzoyl Peroxide (BPO) instead of di-t-butyl hydroperoxide (DTBP), and the other conditions were the same as in example 1, to give the objective product I-1 in 58% yield.
Example 4
Potassium persulfate (K) for oxidizing agent 2 S 2 O 8 ) The procedure of example 1 was repeated except for using the same conditions as in example 1 in place of the di-t-butylhydroperoxide (DTBP), thereby obtaining no target product I-1.
Example 5
The amount of di-t-butylhydroperoxide (DTBP) as an oxidizing agent was 3.0 equivalents, and the yield of the objective product I-1 was 86% by the same conditions as in example 1.
Example 6
The amounts of water and cyclohexane used were 1.5mL/0.5mL, and the other conditions were the same as in example 1, to give a yield of the objective product I-1 of 86%.
Example 7
The amounts of water and cyclohexane used were 1.9mL/0.1mL, and the other conditions were the same as in example 1, to give a yield of the objective product I-1 of 30%.
Example 8
The phase transfer agent was 18-crown-6 (18-crown-6) instead of Sodium Dodecyl Sulfate (SDS), and the other conditions were the same as in example 1 to obtain the objective product I-1 in a yield of 84%.
Example 9
The phase transfer agent was tetrabutylammonium iodide (TBAI) instead of Sodium Dodecyl Sulfate (SDS), and the other conditions were the same as in example 1 to obtain the objective product I-1 in a yield of 82%.
Example 10
The reaction temperature was lowered to 85℃and the other conditions were the same as in example 1 to give the desired product I-1 in a yield of 70%.
As can be seen from the above examples 1 to 10, the optimal reaction conditions were those of example 1, i.e., the oxidizing agent was DTBP (2.0 equiv), the phase transfer agent was SDS (0.2 equiv), the amounts of water and alkane were 1.8mL/0.2mL, and the reaction temperature was 95 ℃. On the basis of obtaining the optimal reaction condition, the invention further selects quinazolinone compounds and alkane compounds with different substituents as raw materials under the optimal reaction condition to develop a controllable free radical cyclization reaction method.
Example 11
40.0mg (0.2 mmol) of the quinazolinone compound represented by formula 1a, 0.2mL of methylcyclohexane represented by formula 2b, 58.5mg (2.0 equiv) of di-tert-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added to a Schlenk flask, and the flask was stirred at 95℃until the starting material disappeared (reaction time was 28 hours) as monitored by TLC. After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the objective product (76% yield, d.r).>20:1), the structural formula of the product is shown as a formula I-2, and the characterization data are as follows: 1 H NMR(500MHz,CDCl 3 )δ:8.28(d,J＝8.0Hz,1H),7.73-7.68(m,2H),7.44-7.41(m,1H),4.33-4.27(m,1H),3.98-3.89(m,1H),3.27-3.22(m,1H),2.58-2.48(m,2H),1.99-1.90(m,2H),1.74-1.70(m,3H),1.53-1.46(m,4H),1.07(s,3H),1.02-0.99(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ:162.4,161.1,149.4,133.9,127.1,126.3,126.0,120.7,44.8,44.4,42.2,41.7,40.2,40.0,29.2,25.8,24.5,23.8；HRMS m/z(ESI)calcd for C 18 H 23 N 2 O([M+H] + )283.1805,found 283.1809。
example 12
To a Schlenk flask, 40.0mg (0.2 mmol) of the quinazolinone compound of formula 1a, 0.2mL of cycloheptane of formula 2c, 58.5mg (2.0 equiv) of di-tert-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added, and then the flask was stirred at 95℃and monitored by TLC for the disappearance of starting material (reaction time of 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (yield 81%), structural formula of the target product was shown in formula I-3, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.33-8.27(m,1H),7.76-7.68(m,2H),7.46-7.42(m,1H),4.31-4.25(m,1H),4.03-3.98(m,1H),3.33-3.25(m,1H),2.50-2.41(m,1H),2.15-2.08(m,1H),1.93-1.88(m,1H),1.76-1.63(m,8H),1.60-1.51(m,4H),1.49-1.46(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:162.3,161.1,149.4,134.0,127.0,126.3,126.1,120.7,44.7,42.0,40.3,36.9,35.8,32.9,28.6,28.5,26.7,26.4,26.2；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O([M+H] + )297.1961,found 297.1955。
example 13
Into a Schlenk flask were charged 40.0mg (0.2 mmol) of the quinazolinone compound represented by formula 1a, 0.2mL of cyclooctane compound represented by formula 2d, 58.5mg (2.0 equiv) of di-tert-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water, howeverThe reaction flask was then stirred at 95℃and monitored by TLC for the disappearance of starting material (reaction time 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the objective product in 77% yield. The structural formula of the product is shown as a formula I-4, and the characterization data are as follows: 1 HNMR(500MHz,CDCl 3 )δ:8.28-8.27(m,1H),7.72-7.67(m,2H),7.44-7.41(m,1H),4.29-4.24(m,1H),4.02-3.96(m,1H),3.32-3.26(m,1H),2.48-2.42(m,1H),2.13-2.08(m,1H),1.94-1.86(m,2H),1.75-1.70(m,4H),1.64-1.60(m,3H),1.53-1.37(m,8H)； 13 C NMR(125MHz,CDCl 3 )δ:162.2,161.0,149.4,134.0,127.1,126.3,126.0,120.8,44.7,41.9,40.3,34.8,33.6,30.5,27.4,27.2,26.8,26.3,25.6,25.2；HRMS m/z(ESI)calcd for C 20 H 27 N 2 O([M+H] + )311.2118,found 311.2112。
example 14
To a Schlenk flask, 40.0mg (0.2 mmol) of a quinazolinone compound represented by formula 1a, cyclododecane (0.2 mL) represented by formula 2e, 58.5mg (2.0 equiv) of di-t-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added, and then the reaction flask was stirred at 95℃to react until the starting material disappeared (reaction time was 28 hours) by TLC. After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the objective product in 71% yield. The structural formula of the product is shown as a formula I-5, and the characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ:8.29-8.27(m,1H),7.74-7.67(m,2H),7.45-7.41(m,1H),4.31-4.25(m,1H),4.04-3.96(m,1H),3.35-3.27(m,1H),2.50-2.41(m,1H),2.09-2.02(m,1H),1.91-1.86(m,1H),1.73-1.69(m,1H),1.53-1.48(m,2H),1.45-1.34(m,21H)； 13 C NMR(100MHz,CDCl 3 )δ:162.2,161.1,149.4,134.0,127.1,126.3,126.1,120.7,44.7,41.8,37.6,31.6,29.7,28.6,26.9,24.7(2),24.0,23.9,23.7,23.0,22.9,22.0,21.4；HRMS m/z(ESI)calcd for C 24 H 35 N 2 O([M+H] + )367.2744,found 367.2748。
example 15
To a Schlenk flask, 40.0mg (0.2 mmol) of the quinazolinone compound of formula 1a, 0.2mL of adamantane of formula 2f, 58.5mg (2.0 equiv) of di-t-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added, and then the reaction flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (52% yield), structural formula of the product was shown in formula I-6, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.27(d,J＝8.0Hz,1H),7.72-7.68(m,2H),7.44-7.40(m,1H),4.30-4.26(m,1H),3.96-3.90(m,1H),3.29-3.23(m,1H),2.60-2.54(m,1H),2.22-2.19(m,1H),2.03-2.00(m,3H),1.91-1.87(m,1H),1.77-1.71(m,3H),1.69-1.60(m,8H),1.38-1.26(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:162.7,161.1,149.5,133.9,127.1,126.3,126.0,120.6,47.1,45.4,44.8,42.9,39.4,37.1,37.0,36.1,32.7,29.8,28.7；HRMS m/z(ESI)calcd for C 22 H 27 N 2 O([M+H] + )335.2118,found 335.2112。
example 16
Into a Schlenk flask, 40.0mg (0.2 mmol) of the quinazolinone compound represented by formula 1a and 2g of the quinazolinone compound represented by formula 2g were introducedN-hexane 0.2mL, di-t-butyl peroxide 58.5mg (2.0 equiv), sodium dodecyl sulfate 11.5mg (0.2 equiv) and water 1.8mL, then the reaction flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the objective product (73% yield, d.r).>20:1), the structural formula of the product is shown as a formula I-7, and the characterization data are as follows: 1 H NMR(500MHz,CDCl 3 )δ:7.32(s,1H),7.21-7.16(m,2H),6.99(d,J＝8.0Hz,1H),6.91(d,J＝7.0Hz,1H),6.76(s,1H),6.72(d,J＝2.5Hz,1H),3.75(s,3H),3.53(d,J＝10.0Hz,1H),3.41(d,J＝10.0Hz,1H),3.11(d,J＝15.5Hz,1H),2.68(d,J＝15.0Hz,1H),2.62-2.57(m,2H),2.30(s,3H),1.27(s,3H),1.20(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ:178.2,158.4,139.2,138.7,137.5,128.6,128.5,128.4,125.5,121.1,117.3,113.2,112.1,59.8,55.3,49.2,41.4,39.2,38.3,24.0,21.5,21.0；HRMS m/z(ESI)calcd for C 22 H 26 NO 2 ([M+H] + )336.1958,found 336.1962。
example 17
40.0mg (0.2 mmol) of the quinazolinone compound represented by formula 1a, 0.2mL of cyclopentane represented by formula 2h, 58.5mg (2.0 equiv) of di-tert-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water were added to a Schlenk flask, and the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (86% yield), structural formula of the product was shown in formula I-8, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.29-8.27(m,1H),7.73-7.67(m,2H),7.45-7.41(m,1H),4.31-4.25(m,1H),4.02-3.97(m,1H),3.27-3.22(m,1H),2.51-2.44(m,1H),2.19-2.14(m,1H),2.03-1.97(m,1H),1.95-1.91(m,1H),1.88-1.82(m,2H),1.70-1.57(m,5H),1.24-1.20(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:162.0,161.0,149.4,134.0,127.0,126.3,126.1,120.7,44.7,43.4,38.3,38.0,33.4,32.0,26.7,25.3,25.1；HRMS m/z(ESI)calcd for C 17 H 21 N 2 O([M+H] + )269.1648,found 269.1642。
example 18
To a Schlenk flask were added 46.0mg (0.2 mmol) of the quinazolinone compound of formula 1b, 0.2mL of cyclohexane of formula 2a, 58.5mg (2.0 equiv) of di-t-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water, and the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (88% yield), structural formula of the product was shown in formula I-9, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:7.64(d,J＝2.8Hz,1H),7.62(d,J＝8.8Hz,1H),7.33-7.30(m,1H),4.30-4.24(m,1H),4.03-3.96(m,1H),3.91(s,3H),3.34-3.27(m,1H),2.49-2.41(m,1H),2.08-2.01(m,1H),1.93-1.83(m,3H),1.75-1.68(m,4H),1.49-1.42(m,2H),1.25-1.17(m,2H),1.11-0.97(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:160.9,160.2,157.9,144.0,128.5,124.2,121.4,105.8,55.8,44.7,41.2,39.8,35.5,34.3,32.1,26.9,26.5,26.4,26.2；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O 2 ([M+H] + )313.1911,found 313.1913。
example 19
To a Schlenk flask were added 46.0mg (0.2 mmol) of a quinazolinone compound represented by formula 1c, 0.2mL of cyclohexane represented by formula 2a, 58.5mg (2.0 equiv) of di-t-butyl peroxide, 11.5mg (0.2 equiv) of sodium dodecyl sulfate and 1.8mL of water, and then the reaction flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (87% yield), structural formula of the product was shown in formula I-10, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.17(d,J＝8.0Hz,1H),7.09(s,1H),7.01(d,J＝7.6Hz,1H),4.29-4.23(m,1H),4.01-3.94(m,1H),3.91(s,3H),3.35-3.28(m,1H),2.49-2.41(m,1H),2.07-2.01(m,1H),1.93-1.84(m,2H),1.78-1.68(m,4H),1.49-1.43(m,2H),1.31-1.23(m,3H),1.09-0.98(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:164.4,163.1,160.7,151.7,127.8,116.3,114.3,107.7,55.6,44.7,41.5,39.7,35.5,34.4,32.0,26.7,26.5,26.4,26.2；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O 2 ([M+H] + )313.1911,found 313.1904。
example 20
To a Schlenk flask were added quinazolinone compound (42.8 mg,0.2 mmol) represented by formula 1d, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: acetic acid)Ethyl ester/n-hexane=7:1) to give the target product (84% yield), the structural formula of the product is shown in formula I-11, and the characterization data are: 1 H NMR(400MHz,CDCl 3 )δ:8.06(s,1H),7.61-7.58(m,1H),7.55-7.51(m,1H),4.26(t,J＝9.2Hz,1H),4.02-3.95(m,1H),3.32-3.25(m,1H),2.47(s,3H),2.44-2.33(m,1H),2.05(t,J＝10.0Hz,1H),1.91-1.84(m,2H),1.78-1.68(m,4H),1.50-1.43(m,2H),1.28-1.24(m,3H),1.08-0.98(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:161.5,161.1,147.3,136.2,135.5,126.8,125.7,120.4,44.7,41.3,39.7,35.5,34.3,32.1,26.8,26.5,26.4,26.2,21.2；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O([M+H] + )297.1961,found 297.1955。
example 21
To a Schlenk flask were added quinazolinone compound (42.8 mg,0.2 mmol) of formula 1e, cyclohexane (0.2 mL) of formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (86% yield), structural formula of the product was shown in formula I-12, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.16(d,J＝8.4Hz,1H),7.49(s,1H),7.26-7.24(m,1H),4.29-4.23(m,1H),4.02-3.94(m,1H),3.34-3.26(m,1H),2.48(s,3H),2.47-2.40(m,1H),2.08-2.01(m,1H),1.93-1.85(m,2H),1.78-1.68(m,4H),1.49-1.42(m,2H),1.27-1.21(m,3H),1.11-0.98(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:162.4,161.0,149.5,145.0,127.7,126.8,126.1,118.3,44.7,41.4,39.8,35.5,34.3,32.1,26.7,26.5,26.4,26.2,21.8；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O([M+H] + )297.1961,found 297.1953。
example 22
To a Schlenk flask were added a quinazolinone compound (46.9 mg,0.2 mmol) represented by formula 1f, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (75% yield), structural formula of the product was shown in formula I-13, and the characterization data were: 1 HNMR(400MHz,CDCl 3 )δ:8.20(d,J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.39-7.37(m,1H),4.29-4.23(m,1H),4.02-3.95(m,1H),3.35-3.27(m,1H),2.50-2.42(m,1H),2.07-1.99(m,1H),1.92-1.83(m,2H),1.79-1.68(m,4H),1.50-1.42(m,2H),1.25-1.21(m,3H),1.11-0.98(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:163.7,160.4,150.4,140.2,127.8,126.7(2),119.2,44.8,41.5,39.7,35.4,34.2,32.1,26.7,26.5,26.3,26.2；HRMS m/z(ESI)calcd for C 18 H 22 ClN 2 O([M+H] + )317.1415,found 317.1417。
example 23
To a Schlenk flask were added quinazolinone compound (55.8 mg,0.2 mmol) represented by formula 1g, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). Reaction stopAfter completion, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (76% yield), structural formula of the product was shown in formula I-14, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.11(d,J＝8.4Hz,1H),7.87(d,J＝1.6Hz,1H),7.54-7.52(m,1H),4.29-4.22(m,1H),4.01-3.94(m,1H),3.35-3.28(m,1H),2.50-2.42(m,1H),2.06-1.99(m,1H),1.92-1.83(m,2H),1.78-1.68(m,4H),1.49-1.41(m,2H),1.34-1.24(m,3H),1.10-0.95(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:163.6,160.5,150.4,129.8,129.4,128.7,127.8,119.6,44.8,41.5,39.7,35.4,34.2,32.1,26.7,26.5,26.3,26.2；HRMS m/z(ESI)calcd for C 18 H 22 BrN 2 O([M+H] + )361.0910,found 361.0902。
example 24
To a Schlenk flask were added quinazolinone compound (42.8 mg,0.2 mmol) represented by formula 1h, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (74% yield), structural formula of the product was shown in formula I-15, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.25(d,J＝7.6Hz,1H),7.73-7.69(m,1H),7.64(d,J＝8.0Hz,1H),7.43-7.39(m,1H),4.27-4.21(m,1H),3.99-3.92(m,1H),3.04-2.98(m,1H),2.11-1.95(m,4H),1.74-1.62(m,5H),1.54-1.47(m,2H),1.26-1.17(m,4H),1.07-0.97(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:162.4,158.5,147.5,134.0,126.8,126.5,126.0,120.2,41.8,40.9,37.5,34.8,34.3,32.2,26.6,26.5,26.3,24.5,19.9；HRMS m/z(ESI)calcd for C 19 H 25 N 2 O([M+H] + )297.1961,found 297.1955。
example 25
To a Schlenk flask were added a quinazolinone compound (45.7 mg,0.2 mmol) represented by formula 1j, cyclohexane (0.2 mL) represented by formula 2a, di-t-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (75% yield), structural formula of the product was shown in formula I-16, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.04(s,1H),7.55-7.50(m,2H),4.26-4.21(m,1H),3.97-3.91(m,1H),3.02-2.96(m,1H),2.47(s,3H),2.11-1.87(m,5H),1.77-1.61(m,6H),1.53-1.46(m,2H),1.23-1.16(m,2H),1.06-0.98(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:162.3,157.6,145.5,136.0,135.5,126.7,125.9,119.9,41.7,40.8,37.5,34.8,34.3,32.2,26.6,26.5,26.3,24.5,21.3,20.0；HRMS m/z(ESI)calcd for C 20 H 27 N 2 O([M+H] + )311.2118,found 311.2112。
example 26
Into a Schlenk flask were added quinazolinone compound (45.7 mg,0.2 mmol) represented by formula 1k, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was filled with waterThe reaction was stirred at 95℃and monitored by TLC for the disappearance of starting material (reaction time 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (75% yield), structural formula of the product was shown in formula I-17, and the characterization data were: 1 H NMR(400MHz,CDCl 3 )δ:8.13(d,J＝8.0Hz,1H),7.44(s,1H),7.24-7.22(m,1H),4.26-4.20(m,1H),3.97-3.90(m,1H),3.01-2.96(m,1H),2.48(s,3H),2.10-1.93(m,4H),1.73-1.60(m,6H),1.53-1.46(m,2H),1.26-1.18(m,3H),1.07-0.97(m,2H)； 13 C NMR(100MHz,CDCl 3 )δ:162.3,158.5,147.6,144.8,127.6,126.5,126.4,117.8,41.7,40.8,37.5,34.8,34.3,32.2,26.6,26.5,26.3,24.5,21.8,20.0；HRMS m/z(ESI)calcd for C 20 H 27 N 2 O([M+H] + )311.2118,found 311.2114。
example 27
To a Schlenk flask were added quinazolinone compound (49.7 mg,0.2 mmol) represented by formula 1l, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (68% yield), structural formula of the product was shown in formula I-18, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.17(d,J＝8.5Hz,1H),7.64(d,J＝2.0Hz,1H),7.36-7.34(m,1H),4.25-4.19(m,1H),3.95-3.90(m,1H),3.01-2.96(m,1H),2.11-1.95(m,4H),1.76-1.59(m,6H),1.51-1.45(m,2H),1.29-1.25(m,3H),1.04-0.97(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:161.7,159.9,148.5,140.1,128.1,126.6,126.4,118.6,41.9,40.8,37.6,34.8,34.2,32.2,26.6,26.4,26.2,24.5,19.9；HRMS m/z(ESI)calcd for C 19 H 24 ClN 2 O([M+H] + )331.1572,found 331.1576。
example 28
To a Schlenk flask were added quinazolinone compound (45.5 mg,0.2 mmol) of formula 1m, cyclohexane (0.2 mL) of formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (60% yield), structural formula of the product was shown in formula I-19, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.27-8.25(m,1H),7.72-7.68(m,1H),7.64(d,J＝8.0Hz,1H),7.42(t,J＝7.5Hz,1H),5.15-5.11(m,1H),3.78-3.73(m,1H),3.15-3.11(m,1H),2.14-2.10(m,1H),1.97-1.81(m,5H),1.73-1.64(m,5H),1.50-1.42(m,3H),1.22-1.15(m,3H),1.02-0.94(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:162.3,160.9,147.4,133.9,127.3,126.9,126.2,120.3,41.4,41.3,40.7,35.2,34.0,33.5,32.2,27.8,27.4,26.7,26.4(2)；HRMS m/z(ESI)calcd for C 20 H 27 N 2 O([M+H] + )311.2118,found 311.2112。
example 29
Into a Schlenk flask were charged a quinazolinone compound (52.5 mg,0.2 mmol) represented by formula 1n, a cyclohexane compound (0.2 mL) represented by formula 2a) Di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), then the reaction flask was stirred at 95 ℃ to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (89% yield), structural formula I-20, as represented by the following data: 1 H NMR(500MHz,CDCl 3 )δ:8.63(d,J＝8.0Hz,1H),8.44(d,J＝7.5Hz,1H),7.81-7.76(m,2H),7.53-7.50(m,1H),7.46-7.42(m,1H),7.39-7.33(m,2H),2.31-2.27(m,1H),2.01-1.98(m,1H),1.58(s,3H),1.44-1.34(m,4H),1.07-1.02(m,1H),0.94-0.88(m,3H),0.83-0.76(m,2H),0.73-0.66(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ:164.2,160.3,147.6,138.9,136.4,134.2,128.3,127.4,126.8,126.6,126.4,122.9,121.3,117.3,48.8,47.3,34.8,34.5,33.5,28.5,26.0,25.9(2)；HRMS m/z(ESI)calcd for C 23 H 25 N 2 O([M+H] + )345.1961,found 345.1953。
example 30
To a Schlenk flask were added a quinazolinone compound (52.5 mg,0.2 mmol) represented by formula 1o, cyclohexane (0.2 mL) represented by formula 2a, di-tert-butyl peroxide (DTBP, 58.5mg,2.0 equiv), sodium dodecyl sulfate (SDS, 11.5mg,0.2 equiv) and water (1.8 mL), and then the flask was stirred at 95℃to react, and the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 28 hours). After the reaction was stopped, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: ethyl acetate/n-hexane=7:1) to give the target product (87% yield), structural formula of the product was shown in formula I-21, and the characterization data were: 1 H NMR(500MHz,CDCl 3 )δ:8.62(d,J＝8.0Hz,1H),8.44(d,J＝8.0Hz,1H),7.81-7.77(m,2H),7.54-7.51(m,1H),7.46-7.43(m,1H),7.39-7.33(m,2H),2.42-2.37(m,1H),2.18-2.15(m,1H),1.62(s,3H),1.37-1.34(m,2H),1.22-1.11(m,5H),0.86-0.81(m,2H)； 13 C NMR(125MHz,CDCl 3 )δ:164.1,160.2,147.6,139.1,136.5,134.3,128.3,127.4,126.8,126.6,126.4,122.9,121.4,117.2,49.4,46.6,37.3,33.8,32.8,27.5,24.8,24.6；HRMS m/z(ESI)calcd for C 22 H 23 N 2 O([M+H] + )331.1805,found 331.1801。
example 31 reaction mechanism control experiment
To the reaction of example 1, 3.0 equivalent of tetramethylpiperidine nitroxide (TEMPO) or 2, 6-di-t-butyl-4-methylphenol (BHT) was added as a radical scavenger, and the yield of the target product of the reaction was almost 0%. Control experiments show that the reaction does go through the free radical reaction process.
From this, the reaction mechanism of the present invention is deduced as shown in the following formula:
the above-described embodiments are merely preferred embodiments of the present invention and are not intended to be exhaustive of the possible implementations of the present invention. Any obvious modifications thereof, without departing from the principles and spirit of the present invention, should be considered to be within the scope of the appended claims.

Claims (8)

1. Alkane C (sp) in aqueous phase 3 ) The preparation method of the polycyclic quinazolinone derivative started by H functionalization is characterized in that the method comprises the steps of adding a quinazolinone compound of a raw material formula 1, alkane of a formula 2, a phase transfer agent and an oxidant into a solvent to react under an air atmosphere to generate the polycyclic quinazolinone derivative of a formula I, wherein the reaction formula is as followsThe following are provided:
wherein R in formula 1 1 Selected from hydrogen, C 1 -C 6 Alkyl, halogen or methoxy; n=1, 2 or 3; in 2Selected from C 5 -C 14 Alkyl of (a);
the oxidant is selected from one or more of di-tert-butyl peroxide, dibenzoyl peroxide and tert-butyl peroxide.
2. The method of claim 1, wherein R is 1 Selected from hydrogen, chlorine, bromine, methyl or methoxy.
3. The method of claim 1, wherein the oxidizing agent is di-t-butyl peroxide.
4. The method according to any one of claims 1-2, wherein the phase transfer agent is selected from one or a mixture of several of sodium dodecyl sulfonate, tetrabutylammonium iodide or 18-crown-6.
5. The method of claim 4, wherein the phase transfer agent is sodium dodecyl sulfonate.
6. The method according to any one of claims 1-2, wherein the solvent is water mixed with an alkane.
7. The process according to any one of claims 1 to 2, wherein the quinazolinone is used in an amount of 0.2mmol, the oxidant is used in an amount of 0.4mmol, the phase transfer agent is used in an amount of 0.04mmol, and the water/alkane is 1.5mL/0.5mL-1.9mL/0.1mL at the beginning of the reaction.
8. The process according to any one of claims 1-2, wherein the reaction temperature is 85-95 o C。
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