CN116082272A - Novel chiral N-heterocyclic carbene catalyst and preparation method and application thereof - Google Patents

Novel chiral N-heterocyclic carbene catalyst and preparation method and application thereof Download PDF

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CN116082272A
CN116082272A CN202310046986.5A CN202310046986A CN116082272A CN 116082272 A CN116082272 A CN 116082272A CN 202310046986 A CN202310046986 A CN 202310046986A CN 116082272 A CN116082272 A CN 116082272A
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李俊龙
邢金盾
陈林
曾荣
刘万聪
李青竹
刘燕青
张翔
黄华
冷海军
赵慧慧
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Abstract

The invention discloses a novel chiral N-heterocyclic carbene catalyst, a preparation method and application thereof, belonging to the technical field of organic chemistry, wherein the preparation method comprises the following steps: obtaining alpha-bromocycloheptanone 2 and taking NiCl 2 (dppp) was dissolved in THF and DIBAL-H solution was added dropwise, after cooling to 0deg.C, phenylacetylene substrate was dissolved in THF and added dropwise to the reaction solution, stirring was carried out at room temperature for 2 hours, after cooling to 0deg.C, borane was dissolved in THF and added dropwise to the reaction solution for reaction to give Compound 4; taking outSubstrate 5, PEPPI-IPr and KOH are dissolved in THF, and compound 4 is dissolved in THF and added dropwise into the reaction solution for degassing to obtain compound 6; then the asymmetric hydrogenation product 7 is obtained, and then the asymmetric hydrogenation product and the alpha-bromo-cycloheptanone 2 are subjected to multi-step reaction to synthesize the target compound 8. The yield of the improved carbene catalyst containing the substituent is greatly improved, and the control of the dr value is larger than that of the previous basic body catalyst; through the innovative process of the application, the method is not only applicable to alkynes of a basic body, but also applicable to substituted alkynes, and is wider in application.

Description

Novel chiral N-heterocyclic carbene catalyst and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to the technical field of organic catalysts and applications thereof.
Background
The N-heterocyclic carbene catalyst is an advantageous small molecular catalyst, is various in types, and can efficiently catalyze multiple types of reactions. The free radical reaction mediated by the N-heterocyclic carbene catalyst is one of the hot spots studied by the current organic chemist, although the type of single electron transfer reaction catalyzed by the N-heterocyclic carbene is gradually increased along with the continuous deep research, application No. 202110721589.4 discloses a chiral N-heterocyclic carbene catalyst and a preparation method and application thereof, the invention adds N-bromosuccinimide and p-toluenesulfonic acid into a round bottom flask, adds 1eq of cycloheptanone after DCM is dissolved, reacts overnight at room temperature, and concentrates and purifies to obtain alpha-bromocycloheptanone 2 after the reaction is completed; 1g of montmorillonite, 10mmol of p-methylaniline and 40mmol of phenylacetylene are weighed and react without a solvent, the reaction is carried out for 8 hours at 140 ℃, after the reaction is completed, the reaction is cooled to room temperature, the reaction is filtered and washed by diethyl ether, the filtrate is collected, concentrated and purified to obtain a target compound 5, and the compound 5 is subjected to asymmetric hydrogenation reduction and then is subjected to multi-step reaction with alpha-bromocycloheptanone 2 to synthesize the target compound 7. The patent can be successfully applied to the amide far-end C (sp 3) -H activation serial cyclization reaction, realizes asymmetric catalysis, and has wide market application prospect.
The defects of the patent are that the yield of the amide distal C (sp 3) -H activated tandem cyclization reaction is low, the dr value is small, and the preparation process of the patent is only applicable to alkyne of a basic body and has limitation in application.
Disclosure of Invention
The invention aims at: the novel chiral N-heterocyclic carbene catalyst and the preparation method and application thereof are provided to solve the problems that the yield of the far-end C (sp 3) -H activation serial cyclization reaction of the amide in the prior art is low, the dr value is small, and in addition, the existing catalyst preparation process is only applicable to alkyne of a basic body and has limitation in application.
The technical scheme adopted by the invention is as follows:
a preparation method of a novel chiral N-heterocyclic carbene catalyst comprises the following steps:
step 1, adding 1eq of cycloheptanone 1,1eq of N-bromosuccinimide and 0.1eq of p-toluenesulfonic acid into a round bottom flask, reacting overnight at room temperature by taking DCM as a solvent, and concentrating and purifying after the reaction is finished to obtain alpha-bromocycloheptanone 2;
step 2, weighing 0.02eq NiCl 2 (dppp) was dissolved in THF and 1.2eq DIBAL-H was added dropwise to obtain a first reaction solution, 1eq phenylacetylene substrate was dissolved in THF and added dropwise to the first reaction solution after cooling to 0deg.C, and stirred at room temperature for 2 hours to obtain a second reaction solution, 3eq borane was dissolved in THF and added dropwise to the second reaction solution after cooling to 0deg.C, and reacted at 80deg.C for 24 hours, and after completion of the reaction, compound 4 was obtained by concentration and purification;
step 3, taking 1eq of substrate 5,0.05eq of PEPSI-IPr and 2.2eq of KOH to be dissolved in THF to obtain a third reaction solution, dissolving 2.2eq of compound 4 in THF, dropwise adding the solution into the third reaction solution, degassing the solution, reacting the solution at 70 ℃ for 12 hours, adding 1.1eq of KOH, reacting the solution for 8 hours, concentrating and purifying the solution after the reaction is finished to obtain a compound 6;
step 4, 0.02eq [ Rh (nbd) 2 in argon atmosphere]BF 4 And 0.044eq DuanPhos are dissolved with DCM and stirred at normal temperature for 20min, then 1eq of compound 6 dissolved with a small amount of DCM (a small amount of DCM means just enough to dissolve compound 6) is added, then MeOH is added to obtain a fourth reaction solution, the fourth reaction solution is reacted in 80atm of hydrogen at 30 ℃ for 48h, and after the reaction is completed, the asymmetric hydrogenation product 7 is obtained by concentration and purification;
step 5, 1eq of asymmetric hydrogenation product 7 is weighed, 20N,1eq of NaOH solution, 1eq of carbon disulfide and 2.0M of DMSO are added, alpha-bromocycloheptanone 2 dissolved by 5.0M of DMSO is added under the condition of 0 ℃, then room temperature reaction is carried out for 12 hours, DCM and water are used for extraction after the reaction is completed, an organic layer is collected, after drying, concentration and purification, 1mL/mmol of ethanol is added for dissolution, 0.1mL/mmol of hydrochloric acid is added for reflux for 1 hour, then cooling and filtration are carried out, the crude product is obtained and purified, 0.25M of glacial acetic acid is added for dissolution of the crude product after purification, and 3.3eq of H is added under the condition of 0 DEG C 2 O 2 After 1H of reaction, the reaction mixture was concentrated, 1.5M MeOH was added to dissolve the mixture, and MeOH/H was added dropwise at 0 ℃ 2 O=2:1 (volume ratio) dissolved 4.1eq NaClO 4 ·H 2 O, then reacting for 30min at room temperature, filtering and drying to obtain the target chiral N-heterocyclic carbene catalyst 8;
the technical route for preparing the novel chiral N-heterocyclic carbene catalyst is as follows:
Figure BDA0004055960890000021
Figure BDA0004055960890000031
in the technical proposal of the application, compared with the catalyst of the basic body in the prior art, the improved carbene catalyst containing substituent groups has obvious improvement on the yield in the amide far-end C (sp 3) -H activated tandem cyclization reactionHigh, from 85% to 99% yield before, and is greater in all control over dr value than the dr value of the prior base bulk catalyst, from 10:1 to 14:1, wherein dr is controlled, possibly as a result of its substituted carbene having a greater steric hindrance than the basic carbene; the prior art uses montmorillonite for reaction, only alkyne of a basic body can be produced, and the application is through innovative technology: weigh 0.02eq NiCl 2 (dppp) was dissolved in THF and 1.2eq DIBAL-H was added dropwise to obtain a first reaction solution, 1eq phenylacetylene substrate was dissolved in THF and added dropwise to the first reaction solution after cooling to 0deg.C, and stirred at room temperature for 2 hours to obtain a second reaction solution, 3eq borane was dissolved in THF and added dropwise to the reaction solution after cooling to 0deg.C, and reacted at 80deg.C for 24 hours, and after completion of the reaction, the compound 4 was obtained by concentration and purification; taking 1eq of substrate 5,0.05eq of PEPSI-IPr and 2.2eq of KOH to be dissolved in THF to obtain a third reaction solution, dissolving 2.2eq of compound 4 in THF, dropwise adding the solution into the third reaction solution, then degassing, reacting for 12 hours at 70 ℃, adding 1.1eq of KOH, then reacting for 8 hours, concentrating and purifying after the reaction is finished to obtain 6, wherein the method is applicable to not only base-body alkyne but also substituted alkyne, and has wider application range and higher process yield.
Key intermediate and target compound in the above reaction route 1 H NMR、 13 C NMR characterization:
alpha-bromocycloheptanone
Figure BDA0004055960890000032
Pale yellow oil, 98% yield
1 H NMR(600MHz,CDCl 3 )δ4.33(dd,J＝9.6Hz,4.8Hz 1H),2.82–2.78(m,1H),2.46–2.41(m,1H),2.34–2.29(m,1H),1.99–1.92(m,2H),1.92–1.86(m,1H),1.74–1.69(m,1H),1.55–1.48(m,2H),1.37–1.30(m,1H).
13 C NMR(151MHz,CDCl 3 )δ206.1,53.7,39.3,34.1,29.4,26.8,24.8.
4-tert-butyl-2, 6-bis (1-phenylvinyl) aniline
Figure BDA0004055960890000033
Colorless oil, yield 95%
1 H NMR(600MHz,CDCl 3 )δ7.37–7.38(m,4H),7.26–7.31(m,6H),7.14(s,2n),5.80(s,2H),5.38(s,2H),3.36(s,2H),1.31(s,9H).
13 C NMR(151MHz,CDCl 3 )δ147.7,140.4,139.6,138.9,128.5,128.0,127.2,127.1,126.5,116.0,33.9,31.6.
4-tert-butyl-2, 6-di ((R) -1-phenylethyl) aniline
Figure BDA0004055960890000041
Pale yellow oil, 92% yield
1 H NMR(600MHz,CDCl 3 )δ7.21(s,1H),7.13–7.16(m,5H),7.05–7.08(m,6H),3.91-3.98(m,2H),3.12(s,2H),1.53(d,J＝7.6Hz,6H),1.27–1.30(m,9H)
13 C NMR(151MHz,CDCl 3 )δ146.0,145.8,140.4,140.2,139.7,139.6,129.1,128.6,128.6,127.4,127.3,126.2,122.3,122.2,40.7,40.4,31.8,31.75,22.4,22.3
2, 6-bis (1- (4-tert-butylphenyl) vinyl) -4-methylaniline
Figure BDA0004055960890000042
Pale yellow oil, yield 90%
1 H NMR(600MHz,CDCl 3 )δ7.23–7.24(m,8H),6.84(s,2H),5.70(s,2H),5.23(s,2H),3.34(s,2H),2.18(s,3H),1.22(t,J＝1.7Hz,18H).
13 C NMR(151MHz,CDCl 3 )δ151.0,146.9,139.1,136.6,130.6,127.8,126.6,126.2,125.4,115.2,34.5,31.3,20.4.
2, 6-bis (R) -1- (4-tert-butyl) phenyl) ethyl) -4-methylaniline
Figure BDA0004055960890000043
Pale yellow oil, 92% yield
1 H NMR(600MHz,CDCl 3 )δ7.14–7.15(m,4H),6.97–6.98(m,4H),6.92(s,2H),3.94(d,J＝6.9Hz,2H),3.15(s,2H),1.49–1.51(m,6H),1.18(s,18H)
13 C NMR(151MHz,CDCl 3 )δ148.9,142.51,139.8,130.2,127.0,126.0,125.5,125.4,39.4,34.3,31.3,22.2,21.2
4-methyl-2, 6-bis (1- (naphthalen-2-yl) vinyl) aniline
Figure BDA0004055960890000051
Colorless oil, 85% yield
1 H NMR(600MHz,CDCl 3 )δ7.75–7.78(m,8H),7.60(d,J＝9.0Hz,2H),7.41–7.44(m,4H),7.05(s,2H),5.92(s,2H),5.48(s,2H),3.41(s,2H),2.33(s,3H).
13 C NMR(151MHz,CDCl 3 )δ147.3,139.2,136.9,133.4,133.1,131.0,128.3,128.2,127.8,127.5,126.9,126.2,126.1,125.8,124.4,116.6,20.4.
4-methyl-2, 6-bis (R) -1-naphthalene-2-ethylaniline
Figure BDA0004055960890000052
Yellow oil, yield 90%
1 H NMR(600MHz,CDCl 3 )δ7.75(d,J＝7.8Hz,2H),7.70–7.72(m,5H),7.59(s,2H),7.37–7.42(m,5H),7.26(d,J＝8.3Hz,2H),7.11(s,2H),4.13(q,J＝7.1Hz,2H),3.30(s,2H),2.40(s,3H),1.66(d,J＝7.6Hz,6H).
13 C NMR(151MHz,CDCl 3 )δ143.3,139.9,133.6,132.2,129.9,128.4,127.6,127.6,126.9,126.4,126.2,125.9,125.4,125.3,40.6,22.0,21.2
3- (4-tert-butyl-2, 6-di ((R) -1-phenylethyl) phenyl) -thiazolo [ d ] cycloheptane perchlorate
Figure BDA0004055960890000053
Yellow oil, 34% yield
1 H NMR(600MHz,CDCl 3 )8.63(s,1H),7.73(s,1H),7.64(s,1H),7.23–7.18(m,3H),7.15–7.11(m,3H),6.74–6.68(m,2H),6.62(d,J＝7.8Hz,2H),3.85(q,J＝7.2Hz,1H),3.37(q,J＝7.2Hz,1H),3.07–2.96(m,1H),2.70–2.61(m,1H),2.00–1.87(m,2H),1.87–1.80(m,1H),1.68–1.59(m,1H),1.57(d,J＝7.2Hz,6H),1.51(s,9H),1.39–1.44(m,1H),1.28–1.12(m,2H),1.02–0.93(m,1H).
13 C NMR(151MHz,CDCl 3 )156.4,155.3,148.1,144.4,143.7,141.3,139.8,138.7,132.5,129.4,128.8,127.6,127.3,126.9,126.0,124.4,123.3,40.9,40.1,35.6,31.3,30.6,29.7,28.0,26.6,26.5,25.0.
3- (2, 6-bis (R) -1- (4-tert-butylphenyl) ethyl) -4-methylphenyl) -5,6,7, 8-tetrahydro-4H-thiazolo [ d ] cyclohepta-ne perchlorate
Figure BDA0004055960890000061
Yellow oil, 29% yield
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.66(s,1H),7.48(s,1H),7.39(s,1H),7.17(d,J＝8.4Hz,2H),7.11(d,J＝8.4Hz,2H),6.60(d,J＝8.4Hz,2H),6.56(d,J＝9.0Hz,2H),3.75(q,J＝7.2Hz,1H),3.28(q,J＝7.2Hz,1H),3.06–2.96(m,1H),2.66–2.60(m,1H),2.57(s,3H),2.34–2.24(m,3H),1.99–1.93(m,1H),1.90–1.83(m,1H),1.78–1.69(m,1H),1.50(d,J＝7.2Hz,3H),1.48(d,J＝7.2Hz,3H),1.23(s,9H),1.21(s,9H),0.99–0.90(m,2H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):155.9,150.2,149.7,148.2,142.1,141.5,141.0,140.6,140.5,138.3,132.4,127.5,126.9,126.8,126.0,125.7,125.4,39.8,39.2,34.3,34.2,33.61,33.57,31.2,31.1,30.4,27.9,26.2,24.3,22.7,21.9.
3- (4-methyl-2, 6-bis (R) -1-naphthalene-2-ethyl) phenyl) -5,6,7, 8-tetrahydro-4H-thiazolo [ d ] cyclohepta-ne perchlorate
Figure BDA0004055960890000062
Pale yellow solid, yield 23%
1 H NMR(600MHz,CDCl 3 )δ(ppm):8.79(d,J＝8.4Hz,1H),7.78–7.72(m,3H),7.66–7.62(m,3H),7.60(s,1H),7.48(s,1H),7.46–7.41(m,4H),7.11(s,1H),7.08(s,1H),6.94(d,J＝9.0Hz,1H),6.85(d,J＝8.4Hz,1H),4.08–3.97(m,1H),3.48(q,J＝7.2Hz,1H),2.88–2.77(m,1H),2.65(s,3H),2.33–2.25(m,1H),1.99–1.87(m,1H),1.63(d,J＝6.6Hz,3H),1.61(d,J＝7.8Hz,3H),1.57–1.41(m,3H),1.14–1.03(m,1H),0.96–0.81(m,2H),0.81–0.70(m,1H).
13 C NMR(151MHz,CDCl 3 )δ(ppm):156.4,148.2,142.6,141.7,14.3,140.8,140.4,139.0,133.3,133.2,132.7,132.3,132.2,129.5,128.5,128.3,127.9,127.5,127.3,126.8,126.7,126.2,126.1,125.5,125.4,124.5,124.3,40.4,40.1,30.4,27.8,26.6,26.3,24.8,22.6,22.2,22.0.
Further, in step 4, the volume ratio of MeOH to DCM was 10:1 (DCM means the sum of the two additions), and the concentration of the fourth reaction solution was 2.0M.
Novel chiral N-heterocyclic carbene catalyst prepared by preparation method of novel chiral N-heterocyclic carbene catalyst, wherein the catalyst is shown as formula (I)
Figure BDA0004055960890000071
Wherein Ar is independently selected from phenyl and R is independently selected from tertiary butyl; ar is independently selected from 4-tert-butylphenyl and R is independently selected from methyl; ar is independently selected from phenyl, R is independently selected from tertiary butyl; ar is independently selected from 2-naphthyl and R is independently selected from methyl.
Further, the catalyst is selected from one of the following structural formulas:
Figure BDA0004055960890000072
the novel chiral N-heterocyclic carbene catalyst is used for the organic reaction mediated by the novel chiral N-heterocyclic carbene catalyst.
The use, the reaction is a novel chiral N-heterocyclic carbene catalyst mediated radical history reaction.
The use, the reaction is a novel chiral N-heterocyclic carbene catalyst mediated asymmetric reaction.
In the technical scheme of the application, DCM: dichloromethane; THF: tetrahydrofuran; DI BAL-H: diisobutyl aluminum hydride; PEPSI-I Pr: [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] (3-chloropyridine) palladium dichloride; meOH: methanol; [ Rh (nbd) 2] BF4: rhodium bis (norbornadiene) tetrafluoroborate; duanPhos: (1R, 1"R,2S,2" S) -2,2 "-di-tert-butyl-2, 3,2",3 "-tetrahydro-1H, 1" H- (1, 1 ") diisophosphole, CAS number 528814-26-8; DMSO: dimethyl sulfoxide.
In summary, due to the adoption of the technical scheme, the beneficial effects of the invention are as follows:
1. compared with the catalyst of the basic body in the prior art, the improved carbene catalyst containing the substituent group has obvious improvement on the yield in the amide far-end C (sp 3) -H activated serial cyclization reaction, the yield is improved to 99% from the previous 85%, and the dr value is controlled to be larger than the dr value of the previous basic body catalyst, and the dr value is 10:1 to 14:1, wherein dr is controlled, possibly as a result of its substituted carbene having a greater steric hindrance than the basic carbene; the method comprises the steps of carrying out a first treatment on the surface of the
2. The prior art uses montmorillonite for reaction, only alkyne of a basic body can be produced, and the application is through innovative technology: weigh 0.02eq NiCl 2 (dppp) was dissolved in THF and 1.2eq of DIBAL-H was added dropwise to give a first reaction solution, which was cooledDissolving 1eq phenylacetylene substrate in THF (tetrahydrofuran) and dropwise adding the solution into the first reaction solution, stirring the solution at room temperature for 2 hours to obtain a second reaction solution, cooling the second reaction solution to 0 ℃, dissolving 3eq borane in THF, dropwise adding the solution into the reaction solution, reacting the solution at 80 ℃ for 24 hours, and concentrating and purifying the solution after the reaction is completed to obtain a compound 4; taking 1eq of substrate 5,0.05eq of PEPSI-IPr and 2.2eq of KOH to be dissolved in THF to obtain a third reaction solution, dissolving 2.2eq of compound 4 in THF, dropwise adding the solution into the third reaction solution, then degassing, reacting for 12 hours at 70 ℃, adding 1.1eq of KOH, then reacting for 8 hours, concentrating and purifying after the reaction is finished to obtain 6, wherein the method is applicable to not only alkyne of a basic body but also substituted alkyne, is wider in application and higher in process yield;
3. the novel chiral N-heterocyclic carbene catalyst has novel application of the mediated free radical decarboxylation alkylation reaction;
4. the novel N-heterocyclic carbene catalyst can well mediate free radical reaction and obtain a reaction product with optical activity, and the preparation method has strong operability, novel synthetic route, high yield and wide market application prospect;
5. the novel chiral N-heterocyclic carbene catalyst has excellent catalytic activity, can obtain a catalytic product with good yield, and can realize moderate enantioselectivity and good diastereoselectivity control.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of product 11 of the present invention;
FIG. 2 shows the nuclear magnetic resonance spectrum of the product 11 of the present invention;
FIG. 3 is a liquid spectrum of the racemic catalytic product 11 of test example 1;
FIG. 4 is a liquid-phase diagram of the catalytic product 11 of the chiral catalyst 8a of test example 1;
FIG. 5 is a liquid-phase diagram of the catalytic product 11 of the chiral catalyst 8b of test example 1;
FIG. 6 is a liquid-phase diagram of the catalytic product 11 of the chiral catalyst 8c of test example 1;
FIG. 7 is a liquid spectrum of the racemate catalytic product 13 of test example 2;
FIG. 8 is a liquid-phase diagram of the catalytic product 13 of the chiral catalyst 8a of test example 2;
FIG. 9 is a liquid-phase diagram of the catalytic product 13 of the chiral catalyst 8b of test example 2;
FIG. 10 is a liquid-phase diagram of the catalytic product 13 of the chiral catalyst 8c of test 2.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Experimental example 1N-heterocyclic carbene catalyzed free radical decarboxylation alkylation of aldehyde participation
As shown in FIGS. 1 to 6, p-bromobenzaldehyde is activated by the N-heterocyclic carbene catalyst of the present invention, reacted with proline derivative 9, the free radical decarboxylated alkylation reaction of aldehyde is catalyzed by N-heterocyclic carbene to obtain alpha-proline acylated product 11, and Cs is obtained by screening the alkali and solvent used in the reaction 2 CO 3 As a base, the product 11 can be obtained in a high yield when reacting in DMSO.
Figure BDA0004055960890000091
Figure BDA0004055960890000092
Test procedure: n-heterocyclic carbene catalyst 8 (0.1 eq), proline derivative 9 (1.0 eq), p-bromobenzaldehyde 10 (2.0 eq) and alkali (0.2 eq) are weighed into a tube, the tube is ventilated three times, and the reaction solvent is added for reaction for 4 hours at 60 ℃. After the reaction, the mixture was extracted and purified by column chromatography, the isolation yield was calculated, and the er value was determined by chiral HPLC.
Catalytic product 11 1 H NMR、 13 C NMR characterization:
Figure BDA0004055960890000101
white solid, yield 60%
1 H NMR(600MHz,CDCl 3 )δ7.86(d,J＝6.9Hz,1H),7.72–7.76(m,1H),7.61(d,J＝8.3Hz,1H),7.56(d,J＝7.6Hz,1H),7.32–7.37(m,3H),7.21(dd,J＝12.1,7.2Hz,1H),7.09–7.10(m,1H),5.22–5.33(m,1H),4.98–5.19(m,2H),3.71–3.74(m,1H),3.57–3.63(m,1H),2.27–2.37(m,1H),1.95–1.96(m,3H).
13 C NMR(151MHz,CDCl 3 )δ(ppm)δ197.5,197.2,154.9,154.1,136.7,136.2,134.3,133.6,133.6,132.0,130.0,129.8,128.6,128.5,128.4,128.2,127.9,127.8,127.8,127.7,,67.1,67.0,61.4,60.9,47.1,46.6,30.8,29.8,24.2,23.4.。
Experimental example 2, distal-amide C (sp 3) -H activated tandem cyclization reaction
As shown in FIGS. 7-10, activation of p-bromobenzaldehyde with the N-heterocyclic carbene catalyst of the present invention, reacting with the amide substrate 12, resulted in successful acquisition of the amide distal C (sp 3 ) H activating the cascade cyclization product 13 by screening the base and solvent used in the reaction for K 2 CO 3 As a base, the product 13 can be obtained in a high yield when reacting in acetonitrile.
Figure BDA0004055960890000102
Figure BDA0004055960890000103
Test procedure: n-heterocyclic carbene catalyst 8 (0.1 eq), amide substrate 12 (1.0 eq), p-bromobenzaldehyde (2.0 eq) and alkali (1.5 eq) were weighed into a sealed tube, ventilated three times and reacted for 12h at 60 ℃ after adding reaction solvent. After the reaction is finished, dibromomethane is used as an internal standard to pass through 1 The yield and dr values were determined by H NMR and the er value was determined by chiral HPLC.
Catalytic product 13 1 H NMR、 13 C NMR characterization:
Figure BDA0004055960890000104
white solid
1 H NMR(600MHz,CDCl 3 )δ8.03(d,J＝7.8Hz,1H),7.54–7.41(m,3H),7.39–7.32(m,3H),7.23(d,J＝7.2Hz,1H),3.43(q,J＝6.6Hz,1H),3.41(s,1H),2.84(s,3H),1.23(d,J＝7.2Hz,3H).
13 C NMR(150MHz,CDCl 3 )δ(ppm)δ165.0,140.7,138.6,132.6,131.7,128.3,128.2,127.8,127.4,126.0,122.4,90.5,44.1,30.2,13.8.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims (7)

1. The preparation method of the novel chiral N-heterocyclic carbene catalyst is characterized by comprising the following steps:
step 1, adding 1eq of cycloheptanone 1,1eq of N-bromosuccinimide and 0.1eq of p-toluenesulfonic acid into a round bottom flask, reacting overnight at room temperature by taking DCM as a solvent, and concentrating and purifying after the reaction is finished to obtain alpha-bromocycloheptanone 2;
step 2, weighing 0.02eq NiCl 2 (dppp) was dissolved in THF and 1.2eq DIBAL-H was added dropwise to obtain a first reaction solution, 1eq phenylacetylene substrate was dissolved in THF and added dropwise to the first reaction solution after cooling to 0deg.C, and stirred at room temperature for 2 hours to obtain a second reaction solution, 3eq borane was dissolved in THF and added dropwise to the second reaction solution after cooling to 0deg.C, and reacted at 80deg.C for 24 hours, and after completion of the reaction, compound 4 was obtained by concentration and purification;
step 3, taking 1eq of substrate 5,0.05eq of PEPSI-IPr and 2.2eq of KOH to be dissolved in THF to obtain a third reaction solution, dissolving 2.2eq of compound 4 in THF, dropwise adding the solution into the third reaction solution, degassing the solution, reacting the solution at 70 ℃ for 12 hours, adding 1.1eq of KOH, reacting the solution for 8 hours, concentrating and purifying the solution after the reaction is finished to obtain a compound 6;
step 4, in argon atmosphere0.02eq[Rh(nbd)2]BF 4 And 0.044eq DuanPhos was dissolved with DCM and stirred at room temperature for 20min, then 1eq of Compound 6 dissolved with a small amount of DCM was added, then MeOH was added to obtain a fourth reaction solution, and the reaction was carried out in 80atm hydrogen at 30℃for 48h, after the completion of the reaction, the asymmetric hydrogenation product 7 was obtained by concentration and purification;
step 5, 1eq of asymmetric hydrogenation product 7 is weighed, 20N,1eq of NaOH solution, 1eq of carbon disulfide and 2.0M of DMSO are added, alpha-bromocycloheptanone 2 dissolved by 5.0M of DMSO is added under the condition of 0 ℃, then room temperature reaction is carried out for 12 hours, DCM and water are used for extraction after the reaction is completed, an organic layer is collected, after drying, concentration and purification, 1mL/mmol of ethanol is added for dissolution, 0.1mL/mmol of hydrochloric acid is added for reflux for 1 hour, then cooling and filtration are carried out, the crude product is obtained and purified, 0.25M of glacial acetic acid is added for dissolution of the crude product after purification, and 3.3eq of H is added under the condition of 0 DEG C 2 O 2 After 1H of reaction, the reaction mixture was concentrated, 1.5M MeOH was added to dissolve the mixture, and MeOH/H was added dropwise at 0 ℃ 2 O=2:1 dissolved 4.1eq NaClO 4 ·H 2 O, then reacting for 30min at room temperature, filtering and drying to obtain the target chiral N-heterocyclic carbene catalyst 8;
the technical route for preparing the novel chiral N-heterocyclic carbene catalyst is as follows:
Figure FDA0004055960880000011
/>
Figure FDA0004055960880000021
2. the method for preparing a novel chiral N-heterocyclic carbene catalyst according to claim 1, characterized in that in step 4, the volume ratio of MeOH to DCM is 10:1, and the concentration of the fourth reaction solution is 2.0M.
3. The novel chiral N-heterocyclic carbene catalyst prepared by the preparation method of the novel chiral N-heterocyclic carbene catalyst according to claim 1 or 2, which is characterized in that the catalyst is shown as a formula (I)
Figure FDA0004055960880000022
Wherein Ar is independently selected from phenyl and R is independently selected from tertiary butyl; ar is independently selected from 4-tert-butylphenyl and R is independently selected from methyl; ar is independently selected from phenyl, R is independently selected from tertiary butyl; ar is independently selected from 2-naphthyl and R is independently selected from methyl.
4. A novel chiral N-heterocyclic carbene catalyst according to claim 3, characterized in that the catalyst is selected from one of the following structural formulas:
Figure FDA0004055960880000023
5. use of the novel chiral N-heterocyclic carbene catalysts according to claims 3 and 4 for the mediated organification of reactions.
6. Use according to claim 5, characterized in that: the reaction is a novel chiral N-heterocyclic carbene catalyst mediated radical history reaction.
7. Use according to claim 5, characterized in that: the reaction is a novel chiral N-heterocyclic carbene catalyst mediated asymmetric reaction.
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