CN105001216A - Quinolizidone preparation method - Google Patents

Quinolizidone preparation method Download PDF

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CN105001216A
CN105001216A CN201510394904.1A CN201510394904A CN105001216A CN 105001216 A CN105001216 A CN 105001216A CN 201510394904 A CN201510394904 A CN 201510394904A CN 105001216 A CN105001216 A CN 105001216A
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diphenylphosphine
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CN105001216B (en
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黄汉民
余慧
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Lanzhou Institute of Chemical Physics LICP of CAS
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Lanzhou Institute of Chemical Physics LICP of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a quinolizidone preparation method. According to the invention, substituted nitrogen heterocyclic allylamine and carbon monoxide are adopted as raw materials, and are subjected to a reaction for 1-24h under a temperature of 60-140 DEG C under the existence of a transition metal catalyst with or without a ligand; a solvent is pumped out, and column chromatography is carried out. The structural formula of substituted nitrogen heterocyclic allylamine is as the following. When X is C, R is selected from the following groups: hydrogen, straight-chain or branched-chain C1-5 alkyl with 5 and 6 sites with benzene rings, and with 3, 4, 5, or 6 site substituted, C1-5 alkoxy, halogen, and hydroxymethyl. When X is N, R is C1-5 straight-chain or branched-chain alkyl, or C1-5 alkoxy. R1 is selected from the following groups: hydrogen, and straight-chain or branched-chain C1-5 alkyl. R2 is selected from the following groups: hydrogen, and straight-chain or branched-chain C1-5 alkyl. R3 is selected from the following groups: straight-chain or branched-chain C2-7 alkyl, and C6-10 aryl. The raw materials and the catalyst for the reaction are cheap and are easy to obtain. The synthesis process is simple; and conditions are mild. The method has low cost and high yield, and is easy to be inductrialized.

Description

A kind of preparation method of quinolizine ketone
Technical field
The present invention relates to a kind of preparation method of quinolizine ketone, specifically be utilize the nitrogen heterocyclic allylamine of replacement and carbon monoxide to be raw material, by transition-metal catalyst catalysis generation carbonylation reaction, obtain the compound of quinolizine ketone structure, belong to organic chemical synthesis technical field.
Background technology
Quinolizine ketone is the compound that a class has special physico-chemical character and synthesis application, such as can derive alkaloid lupinine and table lupin alkaloid.In addition, quinolizine ketone groups is the widely used pharmacophoric group of a class inherently, may be used for the treatment of Alzheimer's disease, type ii diabetes, acquired immune deficiency syndrome (AIDS).Because this kind of use of a compound is special, people also strengthen the research to it in recent years.
The method of synthesis quinolizine ketone is less, mainly contains three kinds of methods: condensation reaction (V. Boekelheide, the J. P. Lodge Jr of (1) 2-pyridineacetate and ethoxymethylidene diethyl malonate j. Am. Chem. Soc., 1951, 73,3681); (2) picoline of alpha-substitution and cyclization (L. Forti, M. L. Gelmi, D. Pocar, the M. Varallo of β, β-dichloropropylene aldehyde hETEROCYCLES, 1986, 24,1401); (3) the Horner – Wadsworth – Emmons of β-carbonyl pyridine and phosphonic acid ester Olefination/cyclization (C. W. Muir, A. R. Kennedy, J. M. Redmond, A. J. B. Watson. org. Biomol. Chem., 2013, 11,3337).Although these methods have higher yield, do not need to use noble metal catalyst, these reactions often need the pre-activate of substrate, and will experience polystep reaction, and practical application is greatly limited.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of succinct quinolizine ketone efficiently.
The preparation method of quinolizine ketone of the present invention, it is characterized in that utilize replace nitrogen heterocyclic allylamine and carbon monoxide be raw material, transition-metal catalyst, have or without part exist under 60-140 oc reacts 1-24 hour, then drains solvent, and column chromatography can obtain quinolizine ketone compound; The structural formula of the nitrogen heterocyclic allylamine of described replacement is as follows:
Wherein: when X is C, R is selected from following groups: hydrogen, 5,6 and phenyl ring and 3,4,5 or 6 straight or branched C replaced 1-5alkyl, C 1-5alkoxyl group, halogen, methylol; When X is N, R is straight or branched C 1-5alkyl, C 1-5alkoxyl group; R 1be selected from following groups: hydrogen, straight or branched C 1-5alkyl; R 2be selected from following groups: hydrogen, straight or branched C 1-5alkyl; R 3be selected from following groups: straight or branched C 2-7alkyl, C 6-10aryl.
The pressure of described carbon monoxide is 1 atm ~ 20 atm.Preferred carbon monoxide pressure is 10 atm.
Described transition-metal catalyst is palladium chloride (PdCl 2), dibrominated palladium (PdBr 2), palladium diiodide (PdI 2), acetonitrile palladium chloride (PdCl 2(CH 3cN) 2), allyl palladium chloride ((allyl) PdCl) 2, two (triphenylphosphine) palladium chloride (PdCl 2(PPh 3) 2), dimethylene acetone palladium (Pd 2(dba) 3), Isosorbide-5-Nitrae-bis-(diphenyl phosphine) butane Palladous chloride (Pd (dppb) Cl 2), 4,5-two diphenylphosphine-9,9-dimethyl xanthene acetonitrile trifluoromethanesulfonic acid palladium (Pd (XantPhos) (CH 3cN) 2(OTf) 2) or (cyclooctadiene) palladium diiodide (PdI 2(cod)).Preferred transition-metal catalyst is palladium diiodide.
The consumption of described transition-metal catalyst is 1% ~ 10% of the nitrogen heterocyclic allylamine molar weight replaced.
Described part is two (diphenylphosphine) ethane (DPPE), two (diphenylphosphine) propane (DPPP), two (diphenylphosphine) butane (DPPB), 1, two (diphenylphosphine) ferrocene (DPPF), 4 of 1'-, two (diphenylphosphine)-9 of 5-, two (diphenylphosphine) phenoxazine (NiXantPhos) of 9-dimethyl xanthene (XantPhos), two (2-diphenylphosphine phenyl) ether (DPEPhos) or 4,6-.Preferred part is 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene (XantPhos).
The consumption of described part is 1.2 equivalents of transition-metal catalyst molar weight.
Described solvent be benzene, toluene, phenylfluoroform, dimethylbenzene, sym-trimethylbenzene or n-methyl-2-pyrrolidone.Preferred solvent is toluene.
The present invention has the following advantages relative to prior art:
Under the catalysis of 1, the metal catalyst that the present invention is industrially cheap and easy to get, reacted by the nitrogen heterocyclic allylamine replaced and carbon monoxide, by the method for carbonylation, only a step can efficiently prepare quinolizine ketone compound, this reaction raw materials and catalyzer cheap and easy to get, synthesis technique is simple, greatly reduces synthesis cost.
2, reaction conditions of the present invention is gentle, simple to operate, productive rate is high, substrate applicability wide ranges, is easy to suitability for industrialized production.
3, reaction raw materials of the present invention and catalyst clean nontoxic, environmental pollution is little.
4, reaction process of the present invention cleans, and meets the requirement of Green Chemistry.
Embodiment
embodiment 1quinolizine ketone 2apreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9.0 mg, 0.025 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 67%.
1 (400 MHz, CDCl 3) δ 9.12 (d, J=7.2 Hz, 1 H), 7.65 (dd, J 1=7.6 Hz, J 2=8.4 Hz, 1 H), 7.46 (d, J=8.8 Hz, 1 H), 7.31-7.35 (m, 1 H), 6.98-7.02 (m, 1 H), 6.64 (t, J=8.8 Hz, 2 H);
13 C NMR(100 MHz, CDCl 3) δ 158.8, 142.8, 138.2, 129.4, 127.4, 125.5, 115.0, 109.2, 103.3;
HRMS(ESI) calcd. for C 9H 8NO [M+H]: 146.0600, found: 146.0602.
embodiment 2quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), Pd (cod) I 2(11.7 mg, 0.025 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 63%.
embodiment 3quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 84%, solvent evaporated, and column chromatography ethyl acetate/petroleum ether (1:2) obtains sterling quinolizine ketone 2a.Product is yellow solid, productive rate 81%.
embodiment 4quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), NiXantPhos (16.5 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 83%.
embodiment 5quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), DPEPhos (16.2 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 42%.
embodiment 6quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL dimethylbenzene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 83%.
embodiment 7quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL sym-trimethylbenzene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 82%.
embodiment 8quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL benzene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 84%.
embodiment 9quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL phenylfluoroforms, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours, adds n-hexadecane as interior mark, and GC yield is 80%.
embodiment 10quinolizine ketone 2apreparation
By pyridine ring allylamine 1a(109 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour, adds n-hexadecane as interior mark, and GC yield is 91%.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2a63mg.Product is yellow solid, productive rate 87%.
embodiment 11quinolizine ketone 2bpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1b(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 3 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2b42mg.Product is yellow solid, productive rate 53%.
1 (400 MHz, CDCl 3) δ 7.45 (t, J=8.0 Hz, 1 H), 7.13 (d, J=8.8 Hz, 1 H), 6.97 (dd, J 1=6.8 Hz, J 2=8.8 Hz 1 H), 6.42-6.47 (m, 3 H), 3.02 (s, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 163.2, 145.1, 142.9, 137.3, 128.3, 124.6, 118.0, 112.4, 103.8, 25.0;
HRMS(ESI) calcd. for C 10H 10NO [M+H]: 160.0757, found: 160.0762.
embodiment 12quinolizine ketone 2cpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1c(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2c70mg.Product is yellow solid, productive rate 88%.
1 (400 MHz, CDCl 3) δ 8.95 (s, 1 H), 7.60 (dd, J 1=8.0 Hz, J 2=8.8 Hz 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.20 (dd, J 1=1.6 Hz, J 2=8.8 Hz, 1 H), 6.58-6.64 (m, 2 H), 2.38 (d, J=0.8 Hz ,3 H);
13 C NMR(100 MHz, CDCl 3) δ 158.5, 141.5, 137.4, 132.5, 125.2, 125.0, 124.6, 108.8, 103.2, 18.7;
HRMS(ESI) calcd. for C 10H 9NNaO [M+Na]: 182.0576, found: 182.0577.
embodiment 13quinolizine ketone 2dpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1d(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2d66.8mg.Product is yellow solid, productive rate 84%.
1 (400 MHz, CDCl 3) δ 9.03 (d, J = 7.6 Hz, 1 H), 7.60 (dd, J 1=7.6 Hz, J 2=8.4 Hz, 1 H), 7.23 (s, 1 H), 6.83 (dd, J 1=1.6 Hz, J 2=7.2 Hz, 1 H), 6.51-6.54 (m, 2 H), 2.40 (s, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 158.7, 143.0, 140.8, 138.3, 126.9, 123.4, 117.9, 107.6, 102.2, 21.2;
HRMS(ESI) calcd. for C 10H 9NNaO [M+Na]: 182.0576, found: 182.0570.
embodiment 14quinolizine ketone 2epreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1e(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2e70mg.Product is yellow solid, productive rate 88%.
1 (400 MHz, CDCl 3) δ 9.08 (d, J=7.6 Hz, 1 H), 7.67 (dd, J 1=8.0 Hz, J 2=8.8 Hz, 1 H), 7.19 (d, J=6.4 Hz, 1 H), 6.92 (t, J=7.2 Hz, 1 H), 6.62-6,69 (m, 2 H), 2.48 (s, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 159.2, 143.0, 137.8, 132.2, 129.3, 125.9, 114.5, 109.1, 100.0, 19.3;
HRMS (ESI) calcd. for C 10H 9NNaO [M+Na]: 182.0576, found: 182.0579.
embodiment 15quinolizine ketone 2fpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1f(118 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2f66.8mg.Product is yellow solid, productive rate 82%.
1 (400 MHz, CDCl 3) δ 9.04 (dd, J 1=2.4 Hz, J 2=5.6 Hz, 1 H), 7.66 (dd, J 1=8.0 Hz, J 2=8.8 Hz, 1 H), 7.50 (dd, J 1=5.2 Hz, J 2=9.6 Hz, 1 H), 7.25-7.29 (m, 1 H), 6.72 (d, J=7.6 Hz, 1 H), 6.65 (d, J=8.8 Hz, 1 H);
13 C NMR(100 MHz, CDCl3) δ 158.3, 158.3, 155.8, 153.4, 140.5, 137.5, 137.5, 127.5, 127.4, 122.6, 122.4, 113.5, 113.1, 109.7, 104.1;
19 F NMR(376 MHz CDCl 3) δ -133.7;
HRMS(ESI) calcd. for C 9H 6FNNaO [M+Na]: 186.0326, found: 186.0326.
embodiment 16quinolizine ketone 2gpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1g(118 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 1 hour.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2g68.5mg.Product is yellow solid, productive rate 84%.
1 (400 MHz, CDCl 3) δ 8.90 (d, J=7.2 Hz, 1H), 7.71 (dd, J 1=7.6 Hz, J 2=8.8 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.88-6.92 (m, 2H), 6.69 (d, J=8.8 Hz, 1H);
13 C NMR(100 MHz, CDCl3) δ 158.4, 156.7, 154.2, 138.1, 135.8, 135.5, 123.6, 123.5, 112.8, 112.7, 111.3, 110.9, 110.7, 97.1, 97.1;
19 F NMR(376 MHz CDCl 3) δ -122.8;
HRMS (ESI) calcd. for C 9H 6FNNaO[M+Na]: 186.0326, found: 186.0323.
embodiment 17quinolizine ketone 2hpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1h(126 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 3 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2h67.1mg.Product is yellow solid, productive rate 75%.
1 (400 MHz, CDCl 3) δ 9.13 (t, J=0.8 Hz, 1 H), 7.65 (dd, J 1=7.6 Hz, J 2=8.8 Hz, 1 H), 7.41 (d, J=9.6 Hz, 1 H), 7.23 (dd, J 1=2.0 Hz, J 2=9.2 Hz, 1 H), 6.64-6.67 (m, 2 H);
13 C NMR(100 MHz, CDCl3) δ 157.9, 140.8, 138.2, 130.6, 126.5, 125.0, 123.8, 110.4, 103.8
HRMS(ESI) calcd. for C 9H 6ClNNaO [M+Na]: 202.0030, found: 202.0023.
embodiment 18quinolizine ketone 2ipreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1i(126 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 3 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2i57.3mg.Product is yellow solid, productive rate 64%.
1 (400 MHz, CDCl 3) δ 9.04 (d, J=7.6 Hz, 1 H), 7.73 (dd, J1=7.6 Hz, J2=8.8 Hz, 1 H), 7.42 (dd, J1=0.8 Hz, J2=7.2 Hz, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 6.89 (t, J=7.6 Hz, 1 H), 6.67 (dd, J1=0.8 Hz, J2=8.8 Hz, 1 H);
13 C NMR(100 MHz, CDCl3) δ 158.7, 140.2, 138.5, 129.5, 128.9, 126.5, 113.3, 110.7, 100.9;
HRMS (ESI) calcd. for C9H6ClNNaO [M+Na]: 202.0030, found: 202.0023.
embodiment 19quinolizine ketone 2jpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1j(124 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 12 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2j63.9mg.Product is yellow solid, productive rate 73%.
1 (400 MHz, CD 3OD) δ 9.00 (d, J=7.6 Hz, 1 H), 7.78 (t, J=8.4 Hz, 1 H), 7.61 (d, J=6.8 Hz, 1 H), 7.18 (t, J=7.2 Hz, 1 H), 6.91 (d, J=7.6 Hz, 1 H), 6.56 (d, J=8.8 Hz, 1 H), 4.82 (s, 2 H);
13 C NMR(100 MHz, CD 3OD) δ 160.7, 142.2, 139.7, 137.2, 128.7, 126.9, 116.7, 109.3, 102.3, 61.6;
HRMS (ESI) calcd. for C 10H 9NNaO 2[M+Na]: 198.0525, found: 198.0524.
embodiment 20quinolizine ketone 2kpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1k(146 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 6 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2k99.6mg.Product is yellow solid, productive rate 91%.
1 (400 MHz, CDCl 3) δ 9.14 (d, J=7.2 Hz, 1 H), 7.68 (t, J=8.4 Hz, 1 H), 7.46 (d, J=6.8 Hz, 1 H), 6.99 (t, J=6.8 Hz, 1 H), 6.72 (d, J=7.6 Hz, 1 H), 6.63 (d, J=8.8 Hz, 1 H), 4.78 (s, 4 H), 3.44 (d, J=0.4 Hz, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 159.1, 141.3, 138.2, 131.9, 128.7, 127.3, 114.1, 109.6, 99.5, 96.1, 65.9, 55.9;
HRMS(ESI) calcd. for C 12H 14NO 3[M+H]: 220.0968, found: 220.0971.
embodiment 21quinolizine ketone 2lpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1l(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 12 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2l73.1mg.Product is yellow solid, productive rate 92%.
1 (400 MHz, CDCl 3) δ 9.19 (d, J=7.6 Hz, 1 H), 7.56 (dd, J 1=9.2 Hz, J 2=18.8 Hz, 2 H), 7.36-7.40 (m, 1 H), 7.00-7.04 (m, 1 H), 6.57 (d, J=8.8 Hz, 1 H), 2.41 (s, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 158.2, 140.6, 140.1, 129.0, 128.0, 122.3, 114.7, 109.4, 108.5, 17.1;
HRMS(ESI) calcd. for C 10H 9NNaO [M+Na]: 182.0576, found: 182.0569.
embodiment 22quinolizine ketone 2mpreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1m(116 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 3 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2m66mg.Product is yellow solid, productive rate 83%.
1 (400 MHz, CDCl 3) δ 8.92 (d, J=7.2 Hz, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.15-7.19 (m, 1 H), 6.79-6.83 (m, 1 H), 6.36 (d, J=10 Hz, 2 H), 2.27 (s, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 158.4, 149.9, 141.7, 129.3, 127.0, 124.8, 114.2, 109.3, 104.7, 21.8;
HRMS(ESI) calcd. for C 10H 10NO [M+H]: 160.0757, found: 160.0750.
embodiment 23quinolizine ketone 2npreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1n(144 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 12 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2n100mg.Product is yellow solid, productive rate 93%.
1 (400 MHz, CDCl 3) δ 9.03 (dd, J 1=0.8 Hz, J 2=7.6 Hz, 1 H), 7.36 (d, J=9.2 Hz, 1 H), 7.24-7.28 (m, 1 H), 6.89-6.92 (m, 1 H), 6.48 (d, J=6.4 Hz, 2 H), 2.61 (t, J=7.6 Hz, 2 H), 1.63-1.71 (m, 2 H), 1.32-1.35 (m, 4 H)，0.88-0.91 (m, 3 H);
13 C NMR(100 MHz, CDCl 3) δ 158.7, 154.6, 141.9, 129.2, 127.2, 125.1, 114.3, 108.8, 104.2, 36.0, 31.5, 29.8, 22.6, 14.1;
HRMS(ESI) calcd. for C 14H 18NO [M+H]: 216.1383, found: 216.1388.
embodiment 24quinolizine ketone 2opreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1o(110 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 21 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2o32.1mg.Product is yellow solid, productive rate 44%.
1 (400 MHz, CDCl 3) δ 8.80 (d, J=1.2 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.72 (dd, J 1=7.6 Hz, J 2=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H);
13 C NMR(100 MHz, CDCl 3) δ 157.4, 152.5, 138.8, 135.6, 130.9, 117.2, 116.0, 105.0;
HRMS(ESI) calcd. for C 8H 7N 2O [M+H]: 147.0553, found: 147.0547.
embodiment 25quinolizine ketone 2ppreparation
Its synthetic route is as follows:
By pyridine ring allylamine 1p(134 mg, 0.5 mmol), PdI 2(9 mg, 0.025 mmol), XantPhos (17.4 mg, 0.03 mmol) adds in 2.0 mL toluene, carbon monoxide (10 atm), 120 oc reacts stopped reaction after 24 hours.Solvent evaporated, column chromatography ethyl acetate/petroleum ether (1:2), obtains sterling quinolizine ketone 2p50.7mg.Product is yellow solid, productive rate 52%.
1 (400 MHz, CDCl 3) δ 9.98 (d, J=8.8 Hz, 1 H), 7.41-7.56 (m, 4 H), 7.26-7.28 (m, 1 H), 7.02 (d, J=9.2 Hz, 1 H), 6.70 (dd, J 1=1.6 Hz, J 2=9.2 Hz, 1 H), 6.46 (dd, J 1=1.6 Hz, J 2=7.2 Hz, 1 H);
13 C NMR(100 MHz, CDCl 3) δ 164.7, 142.1, 137.1, 136.1, 129.5, 128.5, 127.6, 126.5, 126.1, 124.0, 122.4, 117.6, 105.9;
HRMS(ESI) calcd. for C 13H 10NO [M+H]: 196.0757, found: 196.0764。

Claims (10)

1. a preparation method for quinolizine ketone, it is characterized in that utilize replace nitrogen heterocyclic allylamine and carbon monoxide be raw material, transition-metal catalyst, have or without part exist under 60-140 oc reacts 1-24 hour, then drains solvent, and column chromatography can obtain quinolizine ketone compound; The structural formula of the nitrogen heterocyclic allylamine of described replacement is as follows:
Wherein: when X is C, R is selected from following groups: hydrogen, 5,6 and phenyl ring and 3,4,5 or 6 straight or branched C replaced 1-5alkyl, C 1-5alkoxyl group, halogen, methylol; When X is N, R is straight or branched C 1-5alkyl, C 1-5alkoxyl group; R 1be selected from following groups: hydrogen, straight or branched C 1-5alkyl; R 2be selected from following groups: hydrogen, straight or branched C 1-5alkyl; R 3be selected from following groups: straight or branched C 2-7alkyl, C 6-10aryl.
2. the method for claim 1, is characterized in that the pressure of described carbon monoxide is 1 atm ~ 20 atm.
3. method as claimed in claim 2, is characterized in that described carbon monoxide pressure is 10 atm.
4. the method for claim 1, it is characterized in that described transition-metal catalyst is palladium chloride, dibrominated palladium, palladium diiodide, acetonitrile palladium chloride, allyl palladium chloride, two (triphenylphosphine) palladium chloride, dimethylene acetone palladium, 1, two (diphenyl phosphine) butane Palladous chloride, 4 of 4-, two diphenylphosphine-9, the 9-dimethyl xanthene acetonitrile trifluoromethanesulfonic acid palladium of 5-or (cyclooctadiene) palladium diiodide.
5. method as claimed in claim 4, is characterized in that described transition-metal catalyst is palladium diiodide.
6. the method for claim 1, is characterized in that the consumption of described transition-metal catalyst is 1% ~ 10% of the nitrogen heterocyclic allylamine molar weight replaced.
7. the method for claim 1, it is characterized in that described part is two (diphenylphosphine) ethane, two (diphenylphosphine) propane, two (diphenylphosphine) butane, 1, two (diphenylphosphine) ferrocene, 4 of 1'-, two (diphenylphosphine)-9 of 5-, two (diphenylphosphine) phenoxazine of 9-dimethyl xanthene, two (2-diphenylphosphine phenyl) ether or 4,6-.
8. method as claimed in claim 7, is characterized in that described part is 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene.
9. the method for claim 1, is characterized in that the consumption of described part is 1.2 equivalents of transition-metal catalyst molar weight.
10. the method for claim 1, it is characterized in that described solvent be benzene, toluene, phenylfluoroform, dimethylbenzene, sym-trimethylbenzene or n-methyl-2-pyrrolidone.
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CN111116576A (en) * 2019-12-01 2020-05-08 北京师范大学 Quinolizinone compound and preparation method thereof

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