CN111072561A - Organic catalytic synthesis chiral quinoline compound and derivatization method thereof - Google Patents

Organic catalytic synthesis chiral quinoline compound and derivatization method thereof Download PDF

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CN111072561A
CN111072561A CN201911194402.9A CN201911194402A CN111072561A CN 111072561 A CN111072561 A CN 111072561A CN 201911194402 A CN201911194402 A CN 201911194402A CN 111072561 A CN111072561 A CN 111072561A
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nmr
cdcl
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chiral compound
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池永贵
吴树权
刘长益
金智超
郑鹏程
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Guizhou University
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention relates to a chiral compound dihydroquinoline derivative, which is represented by the following general formula (1):
Figure DDA0002294340280000011
wherein the carbon atom marked by is a chiral carbon atom, R1Is alkyl, aryl or substituted phenyl, R2The derivative of the chiral compound dihydroquinoline with the quinoline skeleton is prepared by the asymmetric cyclization reaction of α -bromocinnamaldehyde and o-methylsulfonyl protected aminobenzaldehyde, has good universality, good yield of 80 percent, enantioselectivity of 99:1 and good derivatization reaction.

Description

Organic catalytic synthesis chiral quinoline compound and derivatization method thereof
Technical Field
The invention relates to a preparation method for synthesizing a chiral compound containing a quinoline skeleton by using N-heterocyclic carbene organic micromolecules as a catalyst and derivatization research.
Background
The quinoline skeleton is often present in natural products and non-natural compounds and has good biological activity. Various molecules containing quinoline nucleus have been extensively studied in the fields of antiviral, antibacterial, antifungal, anticancer, and agricultural chemicals. Therefore, the synthesis of quinoline compounds has received a great deal of attention. The preparation method for developing the chiral quinoline derivative with high efficiency and high stereoselectivity has important application value.
Disclosure of Invention
The invention aims to design and synthesize a quinoline framework chiral compound with novel structure, good substrate universality and high enantioselectivity, and further study on derivatization.
The technical scheme of the invention is as follows: a chiral compound dihydroquinoline derivative is represented by the following general formula (1):
Figure BDA0002294340270000011
wherein the carbon atom marked by is a chiral carbon atom, R1Is alkyl, aryl or substituted phenyl, R2Is a halogen atom, a methyl group or a trifluoromethyl group.
The substituent of the substituted phenyl is halogen, methyl, methoxyl or trifluoromethyl.
The halogen atom is fluorine, chlorine, bromine, or methyl.
The preparation method of the chiral compound dihydroquinoline derivative is characterized by comprising the following steps: the method comprises the following steps:
(1) reacting α -bromo-cinnamaldehyde with a chiral carbene catalyst to obtain a α -unsaturated acylazole intermediate I;
(2) deprotonating substituted o-aminobenzaldehyde in an alkali 1, 8-diazabicyclo [5.4.0] undec-7-ene to obtain II and II 'intermediates, and carrying out 1,4 addition reaction on the II and II' intermediates and the intermediate I to obtain an intermediate III;
(3) performing intramolecular cyclization addition, leaving a carbene catalyst to obtain an intermediate IV, and removing carbon dioxide from the intermediate IV to generate a chiral compound dihydroquinoline derivative;
the reaction general formula and the process are as follows:
Figure BDA0002294340270000021
the synthetic route of the substituted o-mesyl protected aminobenzaldehyde is as follows: dissolving substituted anthranilic alcohol S1 in dichloromethane, dropwise adding methanesulfonyl chloride, and then adding pyridine; monitoring the reaction, and after the TLC monitoring reaction is finished, carrying out spin drying to obtain a product S2; dissolving S2 in dichloromethane, adding manganese dioxide, reacting at normal temperature, monitoring reaction condition, filtering after reaction, purifying filtrate by column chromatography, and getting S3;
Figure BDA0002294340270000031
the specific preparation content of the invention is as follows:
(1) catalytically synthesized chiral compound dihydroquinoline derivative
Figure BDA0002294340270000032
(2) Derivatization studies of synthetic dihydroquinolines
Figure BDA0002294340270000041
The method has the advantages that common α -bromocinnamaldehyde and modified o-aminobenzaldehyde are used as raw materials, a series of chiral dihydroquinoline compounds with high stereoselectivity are synthesized through Nitrogen Heterocyclic Carbene (NHC) catalysis, and then a series of derivatization is carried out on the synthesized products.
Detailed description of the preferred embodiments
Examples of the invention are presented below, 26 preparation examples and 7 derivatization studies.
General examples
(1) Synthetic routes to dihydroquinoline derivatives:
Figure BDA0002294340270000042
the preparation implementation method and conditions are as follows:
weighing 0.18mmol of α -bromocinnamaldehyde 1, 0.1mmol of o-aminobenzaldehyde 2 and 0.02mmol of N-heterocyclic carbene catalyst respectively, adding 50mg of 4A molecular sieve, adding the mixture into a 10mL Schlenk reaction tube with a magnetic stirrer, adding 2mL of tetrahydrofuran THF (tetrahydrofuran) solvent and 0.15mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) as alkali, slightly shaking the reaction wall to fully mix the mixture, covering a bottle cap, putting the bottle cap in a 45 ℃ oil bath, fully stirring the mixture for reaction for 14h, monitoring the reaction by TLC, performing spin-drying, fully dissolving a small amount of dichloromethane, performing wet-process sample loading, performing column chromatography separation, and obtaining a target compound by using an eluant of polar petroleum ether and ethyl acetate of 6:1, weighing, calculating the corresponding yield, and representing the compound by a resonance point apparatus, a polarimeter, an NMR (NMR) high resolution Mass Spectrometer (MS) and a High Performance Liquid Chromatography (HPLC).
(2) Derivatization studies were performed on the synthesized chiral dihydroquinolines:
and (3) obtaining a target compound, weighing, and calculating the corresponding yield, wherein the compound is characterized by a melting point instrument, a polarimeter, a nuclear magnetic resonance instrument NMR, a high resolution mass spectrometer HRMS and a high performance liquid chromatograph HPLC.
Preparation method for converting compound 3a into compound 4
Figure BDA0002294340270000051
28.5mg of 3a and 2mg of Pd/C were added to a 25ml clean bottle equipped with a magnetic stirrer. Then, 2ml of ethyl acetate was added thereto, and the air in the system was replaced with a balloon filled with hydrogen gas 4 times under stirring at room temperature. The reaction was carried out for 4 hours, after completion of the TLC monitoring, it was filtered through celite, washed three times with ethyl acetate, spin-dried and dried to give 428.5 mg of compound as a colorless oil in 99% yield.
Process for the preparation of compounds 5 and 6 from Compound 4
Figure BDA0002294340270000061
A25 ml clean bottle equipped with a magnetic stirrer was charged with 0.2mmol of 4,0.01mmol of pyridine and 0.8mmol (70% strength in water) of t-butanol peroxide, and 2ml of acetonitrile was added as solvent, overnight at 80 ℃. After TLC monitoring the reaction was completed, it was spin dried and separated by column chromatography, eluting with polar petroleum ether and ethyl acetate 5:1 to obtain the target compound 5 in 40% yield.
0.1mmol of 4 was placed in a 25ml clean bottle equipped with a magnetic stirrer, nitrogen was replaced, 2ml of toluene was added as solvent, cooled to-20 ℃ and 1.0mmol of red aluminum (65% in toluene) was added dropwise. The reaction was carried out at-20 ℃ for 10 hours, followed by TLC monitoring, ammonium chloride quenching, drying, spin-drying, and column chromatography separation with eluent polar petroleum ether and ethyl acetate 10:1 to give the desired compound 6 in 83% yield.
Preparation method for converting compound 3a into compound 7
Figure BDA0002294340270000062
A25 ml clean bottle equipped with a magnetic stirrer was charged with 0.1mmol of 3a, then 0.3mmol of m-chloroperoxybenzoic acid, and then 2ml of dichloromethane as solvent. The reaction was stirred at room temperature for 5 hours, monitored by TLC, then quenched with sodium bicarbonate and sodium thiosulfate, dried, spun-dried, and separated by column chromatography eluting with polar petroleum ether and ethyl acetate 10:1 to give the title compound 7 in 74% yield.
Preparation method for converting compound 3a into compound 8
Figure BDA0002294340270000071
0.1mmol of 3a was added to a 25ml clean bottle equipped with a magnetic stirrer, 2ml of dichloromethane was added as a solvent, stirring was carried out, and 0.2ml of liquid bromine was added dropwise. The reaction was stirred at room temperature overnight, after TLC monitoring the completion of the reaction, quenched with sodium thiosulfate, dried, spin dried, and separated by column chromatography, eluting with polar petroleum ether and ethyl acetate 5:1 to give the target compound 7 in 70% yield.
Preparation method for converting compound 3a into compound 9
Figure BDA0002294340270000072
A25 ml clean bottle equipped with a magnetic stirrer was charged with 0.1mmol of 3a, followed by 2ml of tetrahydrofuran and 0.5ml of water, followed by 0.15mmol of bromosuccinimide. The reaction was stirred at room temperature overnight, monitored by TLC, washed with saturated sodium chloride, dried, spin-dried, and separated by column chromatography, eluting with polar petroleum ether, ethyl acetate 4:1 to give the target compound 7 in 87% yield.
Preparation method for converting compound 3a into compound 10
Figure BDA0002294340270000073
A25 ml clean bottle equipped with a magnetic stirrer was charged with 0.1mmol of 3a, then 2ml of methanol was added and stirred, and then 0.2mmol of sodium hydroxide was added. The reaction was stirred at room temperature overnight, monitored by TLC, washed with saturated sodium chloride, dried, spin-dried, and separated by column chromatography, eluting with polar petroleum ether and ethyl acetate 10:1 to give the target compound 7 in 97% yield.
The experimental characterization of the synthesized compounds was as follows:
Figure BDA0002294340270000081
D 25[α]＝+437.7(c＝0.3 in CHCl3).
1H NMR(400MHz,CDCl 3 )δ7.53(d,J＝6.8Hz,1H),7.36–7.30(m,2H),7.28–7.15(m,6H),6.81(d,J＝9.6Hz,1H),6.29(dd,J＝9.6,5.9Hz,1H),5.99(d,J＝5.9Hz,1H),2.75(s,3H).
13C NMR(101MHz,CDCl 3)δ137.1,131.9,127.6,127.4,127.0,127.0,126.2,126.2,125.9,125.7,125.5,125.3,55.9,36.7.
HRMS(ESI,m/z):Mass calcd.for C16H16NO2S[M+H]+,286.0896；found 286.0893
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝20.9min,Rt2(minor)＝18.6min；er＝97:3).
Figure BDA0002294340270000082
substituent R1Is o-fluorophenyl, the preparation is carried out in the same manner and under the same conditions as in example I; pale yellow solid, 80% yield, 24.3mg, mp 71-73 ℃.
D[α] 2 5 ＝+204.6(c＝0.1 in CHCl3).
1H 3NMR(400MHz,CDCl)δ7.58(d,J＝8.0Hz,1H),7.23(dd,J＝7.5,1.6Hz,1H),7.18–7.08(m,3H),7.06–6.92(m,2H),6.85(t,J＝7.5Hz,1H),6.64(d,J＝9.4Hz,1H),6.27(d,J＝6.0Hz,1H),6.25–6.16(m,1H),2.72(s,3H).
13 3C NMR(101MHz,CDCl)δ158.2(d,J＝247.9Hz),132.4,128.6,128.5,127.9,127.0(d,J＝3.6Hz),126.8,125.9,125.7,125.7,124.9,124.7,123.0(d,J＝3.4Hz),114.6(d,J＝21.7Hz),51.0(d,J＝2.2Hz),36.9.
19 3F NMR(376MHz,CDCl)δ-115.8.
HRMS(ESI,m/z):Mass calcd.for C16H15FNO2S[M+H]+,304.0802；found 304.0799
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.8mL/min,254nm),Rt1(major)＝20.9min,Rt2(minor)＝17.7min；er＝95:5).
Figure BDA0002294340270000091
D 25[α]＝+356.8(c＝0.4 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.69(d,J＝8.0Hz,1H),7.39–7.29(m,2H),7.24(td,J＝7.5,1.2Hz,1H),7.20–7.11(m,3H),7.05–6.99(m,1H),6.66(d,J＝9.4Hz,1H),6.39(dt,J＝9.4,6.0Hz,2H),2.80(s,3H).
13 3C NMR(101MHz,CDCl)δ137.0,134.0,131.3,129.9,129.2,129.1,127.8,127.7,127.1,127.1,126.7,126.3,125.4,55.1,37.9.
HRMS(ESI,m/z):Mass calcd.for C16H15ClNO2S[M+H]+,320.0505；found 320.0507
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝19.3min,Rt2(minor)＝16.6min；er＝95:5).
Figure BDA0002294340270000101
D 25[α]＝+282.2(c＝1.2 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.70(d,J＝8.1Hz,1H),7.57–7.51(m,1H),7.32(td,J＝8.0,1.6Hz,1H),7.23(td,J＝7.5,1.0Hz,1H),7.17(dd,J＝7.5,1.4Hz,1H),7.13(dt,J＝8.8,3.4Hz,1H),7.09–7.05(m,2H),6.62(dt,J＝6.7,4.0Hz,1H),6.43–6.37(m,2H),2.81(s,3H).
13C 3NMR(151MHz,CDCl)δ139.1,134.2,133.2,129.4,129.1,127.9,127.8,127.6,127.1,126.7,126.6,126.0,125.9,121.0,57.3,38.0.
HRMS(ESI,m/z):Mass calcd.for C16H15BrNO2S[M+H]+,364.0001；found 363.9997
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝20.0min,Rt2(minor)＝17.1min；er＝96:4).
Figure BDA0002294340270000111
D 25[α]＝+358.4(c＝1.3 in CHCl3).
1H 3NMR(600MHz,CDCl)δ7.66(d,J＝8.1Hz,1H),7.28(td,J＝7.9,1.6Hz,1H),7.19(m,2H),7.13(dd,J＝7.5,1.4Hz,1H),7.06(dd,J＝7.7,1.4Hz,1H),6.86(d,J＝8.1Hz,1H),6.73(td,J＝7.6,0.8Hz,1H),6.59(d,J＝9.5Hz,1H),6.34(dt,J＝9.5,6.0Hz,2H),3.89(s,3H),2.80(s,3H).
13 3C NMR(151MHz,CDCl)δ155.4,134.1,128.9,128.6,128.1,128.0,127.6,127.0,126.8,126.5,126.4,124.6,120.5,110.6,55.5,52.9,38.0.
HRMS(ESI,m/z):Mass calcd.for C17H18NO3S[M+H]+,316.1002；found 316.1001
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(minor)＝29.9min,Rt2(major)＝28.5min；er＝5:95).
Figure BDA0002294340270000121
D 25[α]＝+314.7(c＝1.0 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.61–7.54(m,1H),7.25–7.18(m,4H),7.15(d,J＝7.8Hz,1H),7.03(dd,J＝9.9,1.9Hz,1H),6.96–6.78(m,2H),6.29(dd,J＝9.6,6.0Hz,1H),5.98(d,J＝6.0Hz,1H),2.76(s,3H).
13C 3NMR(101MHz,CDCl)δ162.78(d,J＝246.2Hz),δ140.85(d,J＝6.6Hz),132.75,130.01(d,J＝8.1Hz),128.95,127.82,127.03,126.88,126.80,126.50,123.00,122.98,114.99(d,J＝21.1Hz),114.34(d,J＝22.3Hz),56.29(d,J＝1.9Hz).37.79.
19F 3NMR(376MHz,CDCl)δ-112.6.
HRMS(ESI,m/z):Mass calcd.for C16H15FNO2S[M+H]+,304.0802；found 304.0800
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝21.3min,Rt2(minor)＝19.9min；er＝94:6).
Figure BDA0002294340270000122
D 25[α]＝+57.6(c＝0.7 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.59–7.52(m,1H),7.30(s,1H),7.26–7.17(m,6H),6.85(d,J＝9.6Hz,1H),6.29(dd,J＝9.6,6.0Hz,1H),5.96(d,J＝5.9Hz,1H),2.76(s,3H).
13C 3NMR(101MHz,CDCl)δ140.3,134.3,132.6,129.8,129.0,128.2,127.8,127.4,127.1,127.0,126.9,126.8,126.3,125.6,56.2,37.7.
HRMS(ESI,m/z):Mass calcd.for C16H15ClNO2S[M+H]+,320.0342；found 320.0342
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝21.9min,Rt2(minor)＝18.3min；er＝96:4).
Figure BDA0002294340270000131
Substituent R1Is m-trifluoromethylphenyl, the preparation and implementation method and conditions are the same as those of the example I; pale yellow oil, 76% yield, 26.9mg.
D 25[α]＝+290.2(c＝1.1 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.57(dd,J＝6.7,5.2Hz,3H),7.48(d,J＝7.8Hz,1H),7.38(m,J＝7.7Hz,1H),7.26–7.19(m,3H),6.88(d,J＝9.6Hz,1H),6.34(dd,J＝9.6,6.0Hz,1H),6.04(d,J＝6.0Hz,1H),2.77(s,3H).
13C 3NMR(101MHz,CDCl)δ139.4,132.6,130.7(d,J＝32.3Hz),130.8,129.0,129.0,127.8,127.3,127.1,126.9,126.9,126.2,124.9(q,J＝3.7Hz),123.9(q,J＝3.8Hz),123.9(d,J＝272.4Hz),56.2,37.7.
19 3F NMR(376MHz,CDCl)δ-62.5.
HRMS(ESI,m/z):Mass calcd.for C17H15F3NO2S[M+H]+,354.0770；found 354.0768
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝17.2min,Rt2(minor)＝14.4min；er＝96:4).
Figure BDA0002294340270000141
Example I; pale yellow oil, 80% yield, 24.3mg.
D 25[α]＝+273.6(c＝1.4 in CHCl3).
1 3H NMR(400MHz,CDCl)7.45(1H,d,J6.5),7.33–7.03(5H,m),9.46–3.42(11H,m),6.95–6.64(3H,m),6.20(1H,dd,J9.6,5.9),5.89(1H,d,J5.9),2.68(3H,s).
13C NMR(101MHz,CDCl 3 )δ161.47(d,J＝246.7Hz),δ132.80(d,J＝3.1Hz),131.67,128.20,128.11,127.85,126.92,126.04,125.95,125.75,125.71,125.62,114.37(d,J＝21.7Hz),55.26,36.76.
19 3F NMR(377MHz,CDCl)δ-114.04.
HRMS(ESI,m/z):Mass calcd.for C16H15FNO2S [M+H]+,304.0802；found 304.0799
HPLC analysis(Chiralcel IE；25℃,IPA/Hexane＝20/80,0.5mL/min,254nm),Rt1(major)＝21.2min,Rt2(minor)＝20.3min；er＝96:4).
Figure BDA0002294340270000151
Example I; pale yellow oil, 67% yield, 21.4mg.
D 25[α]＝+297.4(c＝1.0 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.58–7.45(m,1H),7.28(s,1H),7.25(d,J＝4.7Hz,1H),7.24–7.18(m,5H),6.84(d,J＝9.6Hz,1H),6.28(dd,J＝9.6,5.9Hz,1H),5.96(d,J＝5.9Hz,1H),2.75(s,3H).
13 3C NMR(101MHz,CDCl)δ136.6,133.9,132.6,128.9,128.8,128.7,127.9,127.0,126.8,126.8,126.8,126.6,56.2,37.8.
HRMS(ESI,m/z):Mass calcd.for C16H15ClNO2S[M+H]+,320.0507；found 320.0506
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝23.4min,Rt2(minor)＝22.1min；er＝97:3).
Figure BDA0002294340270000152
Example I; pale yellow oil, 79% yield, 28.8mg.
D 25[α]＝+341.4(c＝1.2 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.53(d,J＝7.5Hz,1H),7.36(d,J＝8.3Hz,2H),7.20(m,5H),6.84(d,J＝9.6Hz,1H),6.28(dd,J＝9.5,6.0Hz,1H),5.94(d,J＝5.9Hz,1H),2.75(s,3H).
13 3C NMR(101MHz,CDCl)δ137.2,132.7,131.6,129.1,128.9,127.9,127.0,126.9,126.8,126.8,126.5,122.1,56.2,37.8.
HRMS(ESI,m/z):Mass calcd.for C16H15BrNO2S[M+H]+,364.3561；found 364.3561
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝33.9min,Rt2(minor)＝32.2min；er＝99:1).
Figure BDA0002294340270000161
The same as in example I; pale yellow oil, 76% yield, 22.8mg.
D 25[α]＝+402.9(c＝0.9 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.51(dd,J＝6.7,1.5Hz,1H),7.24–7.15(m,5H),7.05(d,J＝8.0Hz,2H),6.80(d,J＝9.6Hz,1H),6.27(dd,J＝9.6,5.9Hz,1H),5.96(d,J＝5.9Hz,1H),2.75(s,3H),2.26(s,3H).
13 3C NMR(101MHz,CDCl)δ137.8,135.1,132.9,129.2,128.6,128.1,127.4,127.3,127.0,126.7,126.5,126.2,56.8,37.8,21.1.
HRMS(ESI,m/z):Mass calcd.for C17H18NO2S[M+H]+,300.1053；found300.1052
HPLC analysis(Chiralcel OD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝19.9min,Rt2(minor)＝18.2min；er＝93:7).
Figure BDA0002294340270000171
Substituent R1Is p-methoxyphenyl, the preparation and implementation method and conditions are the same as in example I; pale yellow oil, 64% yield, 20.2mg.
D 25[α]＝+294.3(c＝0.8 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.53(d,J＝7.4Hz,1H),7.29(s,1H),7.26–7.20(m,4H),6.81(dd,J＝20.8,9.2Hz,3H),6.28(dd,J＝9.6,5.9Hz,1H),5.97(d,J＝5.9Hz,1H),3.76(s,3H),2.77(s,3H).
13 3C NMR(151MHz,CDCl)δ159.4,132.9,130.0,128.7,128.6,128.1,127.5,127.0,126.6,126.5,126.1,113.8,56.6,55.2,37.8.
HRMS(ESI,m/z):Mass calcd.for C17H18NO3S[M+H]+,316.1001；found316.0998
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝35.4min,Rt2(minor)＝31.8min；er＝96:4).
Figure BDA0002294340270000181
Example I; pale yellow oil, 72% yield, 24.2mg.
D 25[α]＝+325.7(c＝1.0 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.78–7.66(m,4H),7.57–7.51(m,2H),7.45–7.37(m,2H),7.23–7.14(m,3H),6.90(d,J＝9.6Hz,1H),6.39(dd,J＝9.6,5.9Hz,1H),6.15(d,J＝5.9Hz,1H),2.79(s,3H).
13 3C NMR(151MHz,CDCl)δ135.4,133.0,132.9,132.9,128.8,128.5,128.1,128.1,127.5,127.1,127.0,126.8,126.7,126.6,126.3,126.2,126.1,125.5,57.0,37.8.
HRMS(ESI,m/z):Mass calcd.for C20H18NO2S[M+H]+,336.1052；found336.1050
HPLC analysis(Chiralcel OD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝31.0min,Rt2(minor)＝26.6min；er＝97:3).
Figure BDA0002294340270000182
D 25[α]＝-279.4(c＝0.7 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.54(d,J＝7.7Hz,1H),7.34(d,J＝1.1Hz,1H),7.25–7.18(m,3H),6.77(d,J＝9.5Hz,1H),6.18(dd,J＝9.2,6.1Hz,2H),6.18(dd,J＝9.2,6.1Hz,2H),6.08(t,J＝5.1Hz,2H),2.80(s,3H).
13 3C NMR(101MHz,CDCl)δ150.3,143.3,133.1,128.7,127.5,127.0,126.9,126.4,126.2,124.5,110.2,109.0,51.7,38.4.
HRMS(ESI,m/z):Mass calcd.for C14H14NO3S[M+H]+,276.0689；found276.0688
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝22.7min,Rt2(minor)＝19.1min；er＝96:4).
Figure BDA0002294340270000191
D 25[α]＝-294.2(c＝0.5 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.62(d,J＝8.0Hz,1H),7.29–7.24(m,1H),7.21(td,J＝7.5,1.2Hz,1H),7.15(dd,J＝7.5,1.5Hz,1H),6.58(d,J＝9.7Hz,1H),6.16(dd,J＝9.7,5.7Hz,1H),4.35(dd,J＝8.9,5.7Hz,1H),2.64(s,3H),1.65–1.59(m,1H),0.95(dd,J＝6.7,4.8Hz,6H).
13 3C NMR(151MHz,CDCl)δ133.4,128.8,128.5,128.3,127.1,126.5,126.5,125.1,60.6,37.4,32.3,19.1,18.6.
HRMS(ESI,m/z):Mass calcd.for C13H14NO2S[M+H]+,252.1053；found252.1051.
HPLC analysis(Chiralcel OD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(minor)＝12.1min,Rt2(major)＝10.6min；er＝1:99)
Figure BDA0002294340270000201
D 25[α]＝+144.2(c＝1.1 in CHCl3).
1H NMR(600MHz,CDCl3)δ7.33–7.29(m,2H),7.25–7.19(m,3H),7.13(t,J＝7.5Hz,1H),7.08(d,J＝6.9Hz,1H),7.02(d,J＝7.3Hz,1H),6.87(d,J＝9.6Hz,1H),6.34(dd,J＝9.6,5.5Hz,1H),5.88(d,J＝5.5Hz,1H),2.79(s,3H),2.26(s,3H)
13C NMR(101MHz,CDCl3)δ137.9,137.2,131.7,127.4,126.9,126.6,126.4,126.3,125.4,125.3,124.9,124.4,55.9,36.6,20.5.
HRMS(ESI,m/z):Mass calcd.for C17H18NO2S[M+H]+,300.1052；found300.1051
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝22.1min,Rt2(minor)＝16.8min；er＝94:6).
Figure BDA0002294340270000202
The same as in example I; pale yellow oil, 72% yield, 21.6mg.
D 25[α]＝+201.1(c＝1.3 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.34(dd,J＝6.1,3.8Hz,3H),7.26–7.19(m,3H),7.08–6.96(m,2H),6.78(d,J＝9.5Hz,1H),6.23(ddd,J＝9.5,5.9,1.6Hz,1H),5.97(d,J＝5.8Hz,1H),2.75(t,J＝3.7Hz,3H),2.28(d,J＝5.5Hz,3H).
13 3C NMR(101MHz,CDCl)δ137.9,137.2,131.7,127.4,126.9,126.6,126.4,126.3,125.4,125.3,124.9,124.4,55.9,36.6,20.5.
HRMS(ESI,m/z):Mass calcd.for C16H18NO2S[M+H]+,300.1053；found300.1052
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝18.8min,Rt2(minor)＝16.8min；er＝96:4).
Figure BDA0002294340270000211
And under the same conditions as in example I; pale yellow oil, 45% yield, 15.9mg.
D 25[α]＝+316.9(c＝1.0 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.81(s,1H),7.43(d,J＝7.5Hz,1H),7.29(ddd,J＝28.9,14.3,9.0Hz,6H),6.87(d,J＝9.6Hz,1H),6.43(dd,J＝9.6,5.9Hz,1H),6.05(d,J＝5.9Hz,1H),2.78(s,3H).
13 3C NMR(151MHz,CDCl)δ137.4,133.4,132.3,130.8,δ130.5(q,J＝32.7Hz),129.9,128.7,128.4,127.2,127.0,125.4,123.7(q,J＝3.8Hz),123.5(q,J＝272.5Hz),123.2(q,J＝3.7Hz),57.08,38.3.
19F 3NMR(565MHz,CDCl)δ-62.5.
HRMS(ESI,m/z):Mass calcd.for C17H15F3NO2S[M+H]+,354.0770；found 354.0768
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝20.8min,Rt2(minor)＝14.4min；er＝96:4)
Figure BDA0002294340270000221
Example I; pale yellow oil, 50% yield, 15.2mg.
D 25[α]＝+351.8(c＝1.2 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.49(dd,J＝9.8,5.1Hz,1H),7.33–7.27(m,3H),7.25–7.21(m,2H),6.90(ddd,J＝8.2,4.7,2.1Hz,2H),6.79(d,J＝9.6Hz,1H),6.38(dd,J＝9.6,5.9Hz,1H),5.99(d,J＝5.9Hz,1H),2.75(s,3H).
13 3C NMR(101MHz,CDCl)δ160.9(d,J＝246.1Hz),137.5,129.7,129.6,129.2,129.1,128.8,128.6(d,J＝2.8Hz),128.5,128.2,127.3,δ125.8(d,J＝2.0Hz),115.3(d,J＝22.7Hz),113.0(d,J＝23.4Hz),56.9,37.6.
19F 3NMR(376MHz,CDCl)δ-114.97.
HRMS(ESI,m/z):Mass calcd.for C16H15FNO2S[M+H]+,304.0802；found 304.0801
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝15/85,0.5mL/min,254nm),Rt1(major)＝17.1min,Rt2(minor)＝15.8min；er＝97:3)
Figure BDA0002294340270000231
D 25[α]＝+263.5(c＝0.9 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.47(d,J＝8.3Hz,1H),7.32–7.26(m,3H),7.24(dt,J＝2.6,1.7Hz,2H),7.20–7.14(m,2H),6.77(d,J＝9.6Hz,1H),6.36(dd,J＝9.6,5.9Hz,1H),5.99(d,J＝5.9Hz,1H),2.77(s,3H).
13 3C NMR(101MHz,CDCl)δ136.5,131.0,130.3,128.3,127.7,127.5,127.5,127.3,127.2,126.2,125.4,124.4,55.9,36.9.
HRMS(ESI,m/z):Mass calcd.for C16H15ClNO2S[M+H]+,320.0506；found 320.0506
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝15/85,0.5mL/min,254nm),Rt1(major)＝20.1min,Rt2(minor)＝18.2min；er＝96:4)
Figure BDA0002294340270000241
D[α] 25＝+197.7(c＝0.9 in CHCl3).
1 3HNMR(400MHz,CDCl)δ7.41(d,J＝8.4Hz,1H),7.35–7.22(m,7H),6.76(d,J＝9.6Hz,1H),6.36(dd,J＝9.6,5.9Hz,1H),5.99(d,J＝5.9Hz,1H),2.77(s,3H).
13 3C NMR(101MHz,CDCl)δ138.7,133.8,132.5,132.3,129.4,129.1,128.6,127.0,124.4,119.4,69.5,64.3,59.2,40.5.
HRMS(ESI,m/z):Mass calcd.for C16H15BrNO2S[M+H]+,364.0001；found 363.9998
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝20.7min,Rt2(minor)＝18.8min；er＝96:4).
Figure BDA0002294340270000242
The same as in example I; pale yellow oil, 42% yield, 14.1mg.
D 25[α]＝+125.1(c＝1.0 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.99(s,1H),7.79–7.74(m,2H),7.64(s,1H),7.47–7.40(m,2H),7.36–7.31(m,2H),7.21(ddd,J＝7.0,4.2,1.3Hz,3H),6.98(d,J＝9.7Hz,1H),6.41(dd,J＝9.7,5.9Hz,1H),6.08(d,J＝5.9Hz,1H),2.77(s,3H).
13 3C NMR(101MHz,CDCl)δ138.3,133.3,131.8,130.7,128.6,128.6,128.2,128.1,127.5,127.4,126.6,126.6,126.5,126.4,125.9,125.2,57.5,37.7.
HRMS(ESI,m/z):Mass calcd.for C20H18NO2S[M+H]+,336.1050；found336.1052
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝35.6min,Rt2(minor)＝28.9min；er＝96:4)
Figure BDA0002294340270000251
Example I; pale yellow oil, 99% yield, 28.5mg.
D 25[α]＝+90.9(c＝0.8 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.73(d,J＝8.2Hz,1H),7.32–7.19(m,6H),7.14–7.06(m,2H),5.54(t,J＝6.7Hz,1H),2.85(s,3H),2.75–2.60(m,2H),2.47(d,J＝5.0Hz,1H),2.06(dd,J＝13.4,5.0Hz,1H).
13 3C NMR(101MHz,CDCl)δ141.8,136.5,131.5,128.8,128.6,127.3,127.2,126.1,124.7,123.5,59.3,39.4,31.7,25.4.
HRMS(ESI,m/z):Mass calcd.for C16H17NO2S[M+H]+,288.1052；found288.1048
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝19.9min,Rt2(minor)＝17.1min；er＝98:2)
Figure BDA0002294340270000261
D 25[α]＝+110.6(c＝0.4 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.98(dd,J＝7.8,1.6Hz,1H),7.79(d,J＝8.4Hz,1H),7.56–7.50(m,1H),7.26–7.17(m,6H),6.04(dd,J＝5.8,2.0Hz,1H),3.34(qd,J＝17.6,4.0Hz,2H),3.11(s,3H)；
13 3C NMR(151MHz,CDCl)δ191.6,140.5,137.6,135.5,128.8,128.0,127.9,126.7,125.0,124.9,122.7,58.1,42.1,40.7；
HRMS(ESI,m/z):Mass calcd.for C16H16NO3S[M+H]+,302.0854；found 302.0844；
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝20/80,0.5mL/min,254nm),Rt1(major)＝22.8min,Rt2(minor)＝19.3min；er＝96:4).
Figure BDA0002294340270000262
Example I; pale yellow oil, 83% yield, 17.3mg.
D 25[α]＝+18.2(c＝1.0 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.41–7.32(m,4H),7.30–7.25(m,1H),7.00(t,J＝7.3Hz,2H),6.65(td,J＝7.4,1.1Hz,1H),6.53(d,J＝7.5Hz,1H),4.43(dd,J＝9.3,3.3Hz,1H),4.03(s,1H),2.92(ddd,J＝16.2,10.6,5.5Hz,1H),2.73(dt,J＝16.4,4.8Hz,1H),2.12(dddd,J＝13.2,5.4,4.6,3.4Hz,1H),1.99(dddd,J＝13.0,10.6,9.4,5.1Hz,1H).
13 3C NMR(151MHz,CDCl)δ144.7,144.6,129.2,128.5,127.3,126.8,126.5,120.8,117.1,113.9,56.2,30.9,26.3.
HRMS(ESI,m/z):Mass calcd.for C16H16NO3S[M+H]+,210.1277；found 210.1275.
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝11.8min,Rt2(minor)＝10.3min；er＝5:95).
Figure BDA0002294340270000271
Example I; pale yellow oil, 74% yield, 22.3mg.
D 25[α]＝+80.8(c＝0.6 in CHCl3).
1 3H NMR(600MHz,CDCl)δ7.62(d,J＝8.1Hz,1H),7.46(dd,J＝7.5,1.5Hz,1H),7.34(td,J＝7.9,1.6Hz,1H),7.25–7.22(m,6H),5.87(d,J＝2.1Hz,1H),4.17(dd,J＝4.2,2.3Hz,1H),4.10(d,J＝4.2Hz,1H),2.93(s,3H).
13C 3NMR(151MHz,CDCl)δ136.1,133.6,130.1,129.8,128.7,128.3,127.6,127.5,126.8,126.3,62.5,55.7,51.3,38.7.
HRMS(ESI,m/z):Mass calcd.for C16H16NO2S[M+H]+,302.0845；found302.0841
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝10/90,0.5mL/min,254nm),Rt1(major)＝34.8min,Rt2(minor)＝27.4min；er＝97:3)
Figure BDA0002294340270000281
Example I; white solid, 70.0% yield, 30.9mg, mp 184-.
D 25[α]＝+51.0(c＝0.3 in CHCl3).
1 3H NMR(400MHz,CDCl)δ8.00(d,J＝9.0Hz,1H),7.58–7.51(m,2H),7.36–7.27(m,6H),6.19(d,J＝2.7Hz,1H),5.54(s,1H),5.29(dd,J＝3.1,2.1Hz,1H),3.26(s,3H).
13C 3NMR(101 MHz,CDCl)δ138.3,135.6,133.8,133.6,128.9,128.7,128.3,127.4,126.4,124.8,120.3,117.0,62.2,51.4,42.3,39.2.
HRMS(ESI,m/z):Mass calcd.for C16H16NO2S[M+H]+,441.9106；found441.9104.
HPLC analysis(Chiralcel IB；25℃,IPA/Hexane＝20/80,0.8mL/min,254nm),Rt1(major)＝30.8min,Rt2(minor)＝33.1min；er＝97:3)
Figure BDA0002294340270000291
Substituent R1Is phenyl, R2For hydrogen, the preparation was carried out under the same conditions and in the same manner as in example I; yellow solid, 87.0% yield, 33.2mg, mp 80-82 ℃.
D[α] 25＝+27.0(c＝0.8 in CHCl3).
1 3H NMR(400MHz,CDCl)δ7.80(dd,J＝2.3,0.9Hz,1H),7.54(ddd,J＝8.7,2.3,0.5Hz,1H),7.48(d,J＝8.7Hz,1H),7.36–7.31(m,3H),7.28–7.24(m,3H),5.69(d,J＝7.3Hz,1H),4.81(dd,J＝8.8,4.5Hz,
1H),4.15(dd,J＝8.8,7.3Hz,1H),2.84(s,3H),2.64(d,J＝4.7Hz,1H).
13 3C NMR(101MHz,CDCl)δ138.7,133.8,132.5,132.3,129.4,129.1,128.6,127.0,124.4,119.4,69.5,64.3,59.2,40.5.
HRMS(ESI,m/z):Mass calcd.for C16H16NO3S[M+H]+,382.0107；found 381.9937.
HPLC analysis(Chiralcel AD-H；25℃,IPA/Hexane＝20/80,0.5mL/min,254nm),Rt1(major)＝35.8min,Rt2(minor)＝25.1min；er＝97:3).
Figure BDA0002294340270000292
Example I; yellow solid, yield 97%.
1H 3NMR(600MHz,CDCl)δ8.21(d,J＝8.6Hz,1H),8.17(dd,J＝8.4,7.1Hz,3H),7.87(d,J＝8.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.72(ddd,J＝8.4,6.9,1.4Hz,1H),7.54–7.50(m,3H),7.46(ddd,J＝7.3,3.9,1.2Hz,1H).
13 3C NMR(151MHz,CDCl)δ157.3,148.2,139.7,136.7,129.7,129.6,129.3,128.8,127.5,127.4,127.1,126.2,119.0.
HRMS(ESI,m/z):Mass calcd.for C15H12N[M+H]+,206.0964；found206.0960
In summary, the present invention is only a preferred embodiment, and is not limited to any form, and any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are still within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.

Claims (5)

1. A chiral compound dihydroquinoline derivative is represented by the following general formula (1):
Figure FDA0002294340260000011
wherein the carbon atom marked by is a chiral carbon atom, R1Is alkyl, aryl or substituted phenyl, R2Is a halogen atom, a methyl group or a trifluoromethyl group.
2. A class of chiral compound dihydroquinoline derivatives according to claim 1, wherein: the substituent of the substituted phenyl is halogen, methyl, methoxyl or trifluoromethyl.
3. A class of chiral compound dihydroquinoline derivatives according to claim 1, wherein: the halogen atom is fluorine, chlorine, bromine, or methyl.
4. A process for the preparation of a dihydroquinoline derivative of the chiral compound of claim 1, characterized in that: the method comprises the following steps:
(1) reacting α -bromo-cinnamaldehyde with a chiral carbene catalyst to obtain a α -unsaturated acylazole intermediate I;
(2) deprotonating substituted o-aminobenzaldehyde in an alkali 1, 8-diazabicyclo [5.4.0] undec-7-ene to obtain II and II 'intermediates, and carrying out 1,4 addition reaction on the II and II' intermediates and the intermediate I to obtain an intermediate III;
(3) performing intramolecular cyclization addition, leaving a carbene catalyst to obtain an intermediate IV, and removing carbon dioxide from the intermediate IV to generate a chiral compound dihydroquinoline derivative;
the reaction general formula and the process are as follows:
Figure FDA0002294340260000021
5. the method for preparing a chiral compound dihydroquinoline derivative according to claim 4, which comprises the following steps: the synthetic route of the substituted o-mesyl protected aminobenzaldehyde is as follows: dissolving substituted anthranilic alcohol S1 in dichloromethane, dropwise adding methanesulfonyl chloride, and then adding pyridine; monitoring the reaction, and after the TLC monitoring reaction is finished, carrying out spin drying to obtain a product S2; dissolving S2 in dichloromethane, adding manganese dioxide, reacting at normal temperature, monitoring reaction condition, filtering after reaction, purifying filtrate by column chromatography, and getting S3;
Figure FDA0002294340260000022
CN201911194402.9A 2019-11-28 2019-11-28 Organic catalytic synthesis chiral quinoline compound and derivatization method thereof Pending CN111072561A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805347A (en) * 2022-05-12 2022-07-29 贵州大学 Organic catalytic synthesis chiral pyrazolo [3,4-b ] pyridone compound and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805347A (en) * 2022-05-12 2022-07-29 贵州大学 Organic catalytic synthesis chiral pyrazolo [3,4-b ] pyridone compound and application thereof
CN114805347B (en) * 2022-05-12 2023-10-20 贵州大学 Organic catalytic synthesis chiral pyrazolo [3,4-b ] pyridone compound and application thereof

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