CN1948310A - 3 position substituted mesoazalene compounds and high efficiency synthesis method - Google Patents

3 position substituted mesoazalene compounds and high efficiency synthesis method Download PDF

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CN1948310A
CN1948310A CN 200610117996 CN200610117996A CN1948310A CN 1948310 A CN1948310 A CN 1948310A CN 200610117996 CN200610117996 CN 200610117996 CN 200610117996 A CN200610117996 A CN 200610117996A CN 1948310 A CN1948310 A CN 1948310A
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indolizine
aryl
compound
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alkyl
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CN100528873C (en
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刘元红
宋智泉
闫彬
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a 3-position substituted indolizine compound and its synthesis method. It is characterized by that said invention uses bromoheterocyclic compound and terminal acetylene hydrocarbon as raw material, and utilizes a bimetallic catalytic system formed from transistion metal catalyst and copper salt to make the above-mentioned raw materials implement catalytic reaction in the presence of proper quantity of alkali so as to obtain the invented indolizine compound with high quality and yield.

Description

The 3-position replaces indolizine compound and high-efficiency synthesis method
Technical field
The present invention relates to contain the indolizine compound and simple and direct, the synthetic method efficiently of the functional group of various ways.Utilize present method in molecule, to introduce multiple heterocyclic group effectively simultaneously,, especially can in molecule, introduce two indolizine groups simultaneously as indoles, thiophene, furans, carbazole, pyrimidine, quinoline etc.
Background technology
Indolizine (Indolizine) is representative a kind of in the heterogeneous ring compound.The indolizine analog derivative that contains indolizine skeleton or part and even Restore All has important biological and pharmaceutical use.Though some bibliographical informations the have been arranged synthetic method of indolizine compound exists mostly that reactions steps is many, total recovery is low, catalyst levels is big even use shortcomings such as normal catalyzer.(summary of relevant indolizine synthetic method is seen Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T.Indolizine, InHouben-Weyl; 1994; Vol.E6b/1,2a, pp 323-450.) in recent years, Gevorgyan group (Kel ' in, A.V.; Stromek, A.W.; Gevorgyan, V.J.Am.Chem.Soc.2001,123,2074; Kim, J.T.; Gevorgyan, V.Org.Lett.2002,4,4697; Kim, J.T.; Butt, J.Gevorgyan, V.J.Org.Chem.2004,69,5638; Kim, J.T.; Gevorgyan, V.J.Org.Chem.2005,70,2054) and patent WO03022846 reported the indolizine compound that the synthetic 3-position of similar method replaces respectively.Reaction is set out by the alkynyl pyridine, under the condition of higher temperature of reaction (being generally 110 ℃) and bigger catalyst levels, with in wait until that good yield obtains target product.In this reaction, the alkynyl pyridine need be prepared by the catalytic Sonogashira linked reaction of palladium, and needs separation and purification, is used for next step cyclization then.The heterogeneous ring compounds such as pyridine bromide of the present invention from simply being easy to get is through directly synthesizing the indolizine of multiple replacement with one step of linked reaction of compounds such as propargyl amine, ether.Alkynyl pyridine original position generates in reaction process, and participate directly in the follow-up annulation, avoid the prior isolation and purification of heterogeneous ring compounds such as alkynyl pyridine, under the reaction conditions of lower catalyst levels and gentleness, obtained the indolizine product of multiple replacement form efficiently, with high yield.This compounds is expected to further be applied in the field such as the synthetic and photoelectric material of medicine.
Summary of the invention
The purpose of this invention is to provide a kind of indolizine compound.
Purpose of the present invention also provide a kind of indolizine compound easy, efficiently by pyridine bromide etc. be simple and easy to the heterogeneous ring compound one-step synthesis that sets out have the method for the indolizine compound of significant application value.
The present invention also provides a kind of have universality and valid approach for the novel heterocyclic compounds that contains multiple aromatic base, heteroaryl etc. in the molecule simultaneously synthetic.
The structural formula of the indolizine compound that 3-of the present invention position replaces is as follows:
Wherein, R 1, R 2, R 3Or R 4=H, C 1-16Alkyl or aryl or R 1And R 2, R 2And R 3, R 3And R 4Between connect the benzo ring;
Y is C or N;
... .. is singly-bound or does not have key;
Z=NR 5R 6Perhaps OR 7Acyl group;
R 5Or R 6=H, molecular formula are R 8The acyl group of CO, R 9Aryl that replaces or heteroaryl, R 9The aryl sulfonyl, the C that replace 1-16Alkyl, benzyl, C 2-C 6Thiazolinyl, alkynyl, C 5-8Cycloalkyl; Perhaps R 5-R 6Between connect into ring in twos;
R 7Be C 1-16Alkyl, R 9Aryl that replaces or heteroaryl, benzyl, C 5-8Cycloalkyl, R 8The acyl group of CO;
R 8Be C 1-16Alkyl, C 1-6Alkoxyl group, R 9The aryl or heteroaryl, benzyl or the C that replace 5-8Cycloalkyl;
R 9Be H, C 1-16Alkyl, C 1-6Alkoxyl group, aryl, nitro, amino, ester group, acyl group or halogen, as F, Cl, Br or I;
Described aryl refers to phenyl, naphthyl, anthryl or fluorenyl; Heteroaryl refers to pyridyl, thienyl, furyl, imidazolyl, pyranyl, pyrimidyl, indyl, carbazyl, thiazolyl, quinolyl, isoquinolyl, indolizine base, benzothienyl, benzofuryl or benzothiazolyl.
The reaction formula of the inventive method is as follows:
Promptly from simply be easy to get, molecular formula is Bromo heterogeneous ring compound and molecular formula be
Figure A20061011799600073
Terminal alkyne set out, in the presence of equivalent or excessive alkali, carry out catalyzed reaction with the bimetallic catalytic system that transition-metal catalyst and mantoquita are formed, well to obtain target compound to outstanding yield.
Institute responds and all carries out in organic solvent, can select benzene,toluene,xylene, N for use, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE (DMA), tetrahydrofuran (THF), diethylamine, triethylamine, 1,4-is to the organic solvents such as mixed solvent of oxygen six rings, acetonitrile dimethyl sulfoxide (DMSO), hexamethylphosphoramide or above-mentioned solvent.
Transition-metal catalyst can be Pd (PPh 3) 4, Pd (PPh 3) 2Cl 2Or Ni (PPh 3) 2Cl 2Deng, consumption is 0.1mol%～20mol%.Mantoquita can be CuI, CuCl, CuBr, neutralized verdigris or fluoroform sulphonyl copper etc., consumption is that 1mol%～200mol%. alkali can be mineral alkali or organic bases, described mineral alkali can be oxyhydroxide, carbonate, supercarbonate or the phosphoric acid salt mineral alkali of monovalence metal, as K 2CO 3, Na 2CO 3, NaHCO 3, NaOCOCH 3, KOH or Cs 2CO 3Deng.Described organic bases is the organic amine compound that has lone-pair electron, as diethylamine, triethylamine, 1, and 8-diazabicylo [5.4.0]-7-hendecene (DBU), triethylene diamine, pyridine or piperidines or tetramethyleneimine etc.
In the method for the present invention, the mol ratio of described bromo heterogeneous ring compound, terminal alkyne, transition-metal catalyst, mantoquita, alkali is followed successively by: 1: 1-1.5: 0.005-0.2: 0.01-2: 3-6.
Reaction times is 1 to 96 hour, is recommended as 1-30 hour.Temperature of reaction is a room temperature to 130 ℃.
The purification of the product of the inventive method can be used recrystallization with separating, thin-layer chromatography, and methods such as column chromatography and underpressure distillation are separated.Recommend with thin-layer chromatography and column chromatography method.Used developping agent is the mixed solvent of polar solvent and non-polar solvent.The developping agent of recommending can be ether-sherwood oil, ethyl acetate-sherwood oil, ethyl acetate-normal hexane or Virahol-sherwood oil etc.
The present invention utilizes bromo heterogeneous ring compound and terminal alkyne, especially the terminal alkyne that contains functional group is at transition metal-catalyzed continuous mutually down carry out coupling and cyclization, thereby obtain the indolizine of multiple replacement in the mode of " one kettle way ", has the reaction conditions gentleness, easy to operate, the yield height, generally can reach 60-99%, the key intermediate alkynyl pyridine that generates in the reaction need not to separate, advantages such as recirculation reaction directly take place in system, also the amplification of easy handling process and realization suitability for industrialized production.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention
Embodiment 1:2-bromopyridine and methyl rubigan propargylamine are at transition-metal catalyst
And the coupling-cyclization under the existence of mantoquita
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmol methyl rubigan propargylamine, N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmolCuI, 1.5mmol DBU, reaction system is warming up to 80 ℃ and stirs 6h, stops heating, is chilled to room temperature, add the shrend reaction of going out, diatomite filtration, filtrate is used ethyl acetate extraction, anhydrous magnesium sulfate drying, concentrate, column chromatography (alkali alumina, sherwood oil: ethyl acetate=drip washing in 30: 1) get 3-(methyl rubigan) amido indolizine, yield 74%.
N-(4-chloro-phenyl-)-3-indolizine base methylamine
1H NMR (CDCl 3, Me 4Si) δ 3.30 (s, 3H), 6.38-6.45 (m, 4H), 6.58 (d, J=4.2Hz, 1H), 6.62-6.67 (m, 1H), 7.08-7.12 (m, 2H), 7.37 (d, J=9.6Hz, 1H), 7.47 (d, J=6.9Hz, 1H). 13C NMR (CDCl 3) δ 39.38,97.56,108.94,110.33,114.10,116.73,119.41,120.99,123.06,127.03,128.95,129.83,147.08.HRMS (EI) calculated value C 15H 13N 2Cl256.0767, measured value 256.0761.
Figure A20061011799600101
N-(4-p-methoxy-phenyl)-3-indolizine base methylamine
(ethyl acetate: sherwood oil=1: 100) obtain product, yield is 76% to alkalescence alchlor column chromatography for separation.
1H NMR (CDCl 3, Me 4Si) δ 3.29 (s, 3H), 3.70 (s, 3H), 6.37-6.47 (m, 4H), 6.56-6.64 (m, 2H), 6.72-6.76 (m, 2H), 7.35 (d, J=9.3Hz, 1H), 7.53 (d, J=6.9Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 39.76,55.58, and 97.30,108.23,109.97,114.38,114.61,116.30,119.25,121.19,128.52,129.44,142.73,152.50; HRMS (EI) calculated value for C 16H 16N 2O 252.1263, measured value 252.1268.
Figure A20061011799600102
N-phenyl-3-indolizine base methylamine
(ethyl acetate: sherwood oil=1: 100) obtain product, yield is 88% to alkalescence alchlor column chromatography for separation.
1H NMR (CDCl 3, Me 4Si) δ 3.31 (s, 3H), 6.37-6.44 (m, 2H), 6.48-6.51 (m, 2H), 6.59 (d, J=3.9Hz, 1H), 6.62-6.65 (m, 1H), 6.76 (t, J=7.2Hz, 1H), 7.13-7.19 (m, 2H), 7.36 (d, J=9.6Hz, 1H), 7.51 (d, J=6.9Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 39.20,97.43, and 108.87,110.10,112.89,116.53,118.13,119.32,121.18,127.59,129.14,129.69,148.41; HRMS (EI) calculated value C 15H 14N 2222.1157, measured value 222.1157.
Resulting (N-the substituted aryl)-3-indolizine of method base methylamine can be by the following apparent synthetic compound (referring to patent WO03022846) that obtains having anti-tumor activity, shown in the following reaction formula thus.
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmolN-allyl group-N-(2-propargyl)-aniline, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI, 1.5mmol DBU, be warming up to 80 ℃ and stir 12h, be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying, concentrate, column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 100) get 102mg 3-(N-allyl group-N-phenyl amino)-indolizine, yield 82%.
3-(N-allyl group-N-phenyl amino)-indolizine
Column chromatography (alkali alumina, sherwood oil: ethyl acetate=drip washing in 50: 1), obtain glassy yellow liquid.
1H?NMR(CDCl 3，Me 4Si)δ4.29(d，J＝5.1Hz，2H)，5.16-5.20(m，1H)，5.26-5.33(m，1H)，5.92-6.04(m，1H)，6.41-6.49(m，4H)，6.63-6.69(m，2H)，6.76(t，J＝7.2Hz，1H)，7.12-7.18(m，2H)，7.38(d， J＝9.0Hz，1H)，7.58(dd，J＝6.9Hz，0.9Hz，1H).
13C NMR (CDCl 3) δ 54.48,97.45,109.98,110.13,113.24,116.65,116.96,118.22,119.32,121.19,126.22,129.17,129.89,133.99,147.50.HRMS (EI) calculated value C 17H 16N 2248.1313, measured value 248.1311.
Synthesizing of embodiment 3:3-(N, N-diphenyl amino)-indolizine
Figure A20061011799600121
In standard Schlenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmolN-phenyl-N-(2-propargyl)-aniline, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 2 hours, and be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 100) get 139 milligrams of yellow-green colour solids, yield is 98%.
3-(N, N-diphenyl amino)-indolizine
Alkalescence alchlor column chromatography for separation (ethyl acetate: sherwood oil=1: 100) obtain the yellow-green colour solid.
1H NMR (CDCl 3, Me 4Si) δ 6.37-6.42 (m, 1H), 6.46 (d, J=4.2Hz, 1H), 6.61-6.67 (m, 2H), 6.92-6.99 (m, 6H), 7.17-7.22 (m, 4H), 7.37 (d, J=9.0Hz, 1H), 7.65 (dd, J=7.5Hz, 1.2Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 98.03,110.48, and 110.93,116.73,119.32,120.45,120.79,122.21,125.51,129.22,129.94,146.11; Anal. calculated value C 20H 16N 2: C, 84.48; H, 5.67; N, 9.85 measured value C, 84.38; H, 5.76; N, 9.78.
Embodiment 4:N, N-phenylbenzene-pyrrolo-[1,2-a] pyrimidine-6-amine synthetic
Figure A20061011799600131
In standard Schlenk pipe, add 0.5mmol 2-bromo pyrimi piperidine, 0.5mmolN-phenyl-N-(2-propargyl)-aniline, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 2 hours, and be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 4) get 67 milligrams of yellow solids, yield is 47%.
N, N-phenylbenzene pyrrolo-[1,2-a] pyrimidine-6-amine
1H NMR (CDCl 3, Me 4Si) δ 6.44 (dd, J=6.9Hz, 3.6Hz, 1H), 6.69 (d, J=4.2Hz, 1H), 6.83 (d, J=4.5Hz, 1H), 6.95-7.02 (m, 6H), 7.20-7.26 (m, 4H), 7.83-7.86 (m, 1H), 8.08 (dd, J=3.9Hz, 1.8Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 98.14,106.49, and 113.12,120.57,122.63,123.26,127.43,129.34,137.07,142.62,145.65; Anal. calculated value C 19H 15N 3: C, 79.98; H, 5.30; N, 14.73; Measured value C, 79.84; H, 5.18; N, 14.67.
Synthesizing of embodiment 5:9-(3-indolizine base)-carbazole
Figure A20061011799600132
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmol9-(2-propargyl)-carbazole, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmolCuI, 1.5mmol DBU, reaction system is warming up to 80 ℃ and stirs 3h, be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying, concentrate, column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 100) get 83mg 9-(3-indolizine base)-carbazole, yield 59%.
9-(3-indolizine base)-carbazole
Alkalescence alchlor column chromatography for separation (ethyl acetate: sherwood oil=1: 50) obtain bright green liquid.
1H NMR (C 6D 6, Me 4Si) δ 5.83 (t, J=6.9Hz, 1H), 6.34 (dd, J=9.0Hz, 6.9Hz, 1H), 6.53 (d, J=4.2Hz, 1H), 6.73 (d, J=4.2Hz, 1H), 6.79 (d, J=7.2Hz, 1H), 6.82-6.85 (m, 1H), 7.14-7.24 (m, 6H), 8.02-8.05 (m, 2H). 13C NMR (C 6D 6) δ 98.82,110.49,110.90,112.36,116.52,117.73,119.60,120.69,120.95,121.62,124.05,126.71,131.91,141.99.HRMS (EI) calculated value C 20H 14N 2282.1157, measured value 282.1155.
Synthesizing of embodiment 6:N-methyl-N-phenyl-pyrrolo-[1,2-a] quinoline-1-amine
Under nitrogen protection, add 0.5mmol 2-bromoquinoline, 0.5mmol N-methyl-N-propargyl aniline and 2 milliliters of N,N-dimethylacetamide successively, stir to clarify under the room temperature to 25 milliliters of Schlenk reaction tubess.Add 0.01mmol PdCl then successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 2 hours.The TLC detection reaction finishes, and adds entry to reaction solution, ethyl acetate extraction three times.Merge organic phase, anhydrous magnesium sulfate drying, solvent is removed in decompression.Product uses alkaline alchlor column chromatography for separation, and (ethyl acetate: sherwood oil=1: 100), get 126 milligrams of yellow-green colour oily liquids, yield is 93%.
N-methyl-N-phenyl-pyrrolo-[1,2-a] quinoline-1-amine alkalescence alchlor column chromatography for separation (ethyl acetate: sherwood oil=1: 100), overall yield 93%I.
1H NMR (CDCl 3, Me 4Si) δ 3.29 (s, 3H), 6.51-6.54 (m, 2H), 6.64-6.67 (m, 2H), 6.75-6.80 (m, 1H), 6.96 (d, J=9.3Hz, 1H), 7.15-7.30 (m, 5H), 7.57 (dd, J=7.5Hz, 1.5Hz, 1H), 8.26-8.29 (m, 1H); 13C NMR (CDCl 3, Me 4Si) δ 39.36,101.47, and 109.93,113.26,115.86,118.31,119.02,119.25,123.41,124.91,127.66,128.10,129.11,129.18,133.46,134.18,148.86; HRMS (EI) calculated value C 19H 16N 2272.1313, measured value 272.1311.
Embodiment 7:N, N-phenylbenzene-pyrrolo-[1,2-a] quinoline-1-amine synthetic
In standard Schlenk pipe, add 0.5mmol 2-bromoquinoline, 0.5mmolN phenyl-N-(2-propargyl)-aniline, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 2 hours, be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 100), get 153 milligrams of oyster solids, yield is 92%.
N, N-phenylbenzene-pyrrolo-[1,2-a] quinoline-1-amine
Column chromatography (alkali alumina, sherwood oil: ethyl acetate=drip washing in 100: 1) get the oyster solid.
1H NMR (CDCl 3, Me 4Si) δ 6.55 (d, J=3.6Hz, 1H), 6.59 (d, J=3.9Hz, 1H), 6.90-6.95 (m, 3H), 7.07-7.10 (m, 4H), 7.15-7.28 (m.7H), 7.53 (dd, J=7.8Hz, 1.8Hz, 1H), 8.61 (dd, J=7.8Hz, 0.9Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 101.85,112.61, and 116.31,119.14,119.16,120.49,122.23,123.53,124.95,127.47,128.02,129.21,129.63,130.86,133.98,146.50; Anal. calculated value C 24H 18N 2: C, 86.20; H, 5.43; N, 8.38; Measured value C, 86.32; H, 5.44; N, 8.30.
Synthesizing of embodiment 8:N-(3-indolizine base)-N-phenyl-2-thenoyl amine
1, raw material synthetic:
Figure A20061011799600161
Synthesizing of N-(2-propargyl)-aniline
The 10mmol propargyl bromide is joined in DMF (20mL) solution of 20mmol aniline, stir and add the 10mmol Anhydrous potassium carbonate down, add the shrend reaction of going out behind the 6h, extracted with diethyl ether is washed twice, anhydrous sodium sulfate drying, concentrate column chromatography (silica gel, sherwood oil: ethyl acetate=drip washing in 15: 1), get 1.17g N-(2-propargyl)-aniline, yield 90%.
Figure A20061011799600162
2, N-phenyl-N-(2-propargyl)-2-thenoyl amine synthetic
In standard Schrenk pipe, add 2mmol N-(2-propargyl)-aniline, 10mL tetrahydrofuran (THF), 2mmol 2-thiophene chloride under the room temperature nitrogen protection successively; the 15min afterreaction is complete; saturated sodium bicarbonate solution cancellation reaction; ethyl acetate extraction; anhydrous sodium sulfate drying concentrates column chromatography (silica gel; sherwood oil: ethyl acetate=drip washing in 3: 1) get 420mg N-phenyl-N-(2-propargyl)-2-thenoyl amine, yield 87%.
1H NMR (CDCl 3, Me 4Si) δ 2.26 (t, J=2.4Hz, 1H), 4.62 (d, J=2.4Hz, 2H), 6.77-6.79 (m, 2H), 7.30-7.36 (m, 3H), 7.41-7.45 (m, 3H). 13C NMR (CDCl 3) δ 40.14,72.38,78.66,126.64,128.79,128.94,129.65,131.14,132.70,137.25,141.76,162.03.HRMS (EI) calculated value C 14H 11NOS 241.0561, measured value 241.0566.
3, N-(3-indolizine base)-N-phenyl-2-thenoyl amine synthetic
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmolN-phenyl-N-(the bright base of 2-alkynes)-2-thenoyl amine, 2mL N,N-dimethylacetamide (molecular sieve drying is heavily steamed processing), 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol cuprous iodide, 1.5mmol DBU (1,8-diazacyclo [5.4.0] hendecene-7), reaction system is warming up to 80 ℃ and stirs 6h, stop heating, be chilled to room temperature, add the shrend reaction of going out, diatomite filtration, filtrate is used ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography (alkali alumina, sherwood oil: ethyl acetate=drip washing in 10: 1) get 114mg N-(3-indolizine base)-N-phenyl-2-thenoyl amine, yield 71%.
N-(3-indolizine base)-N-phenyl-2-thenoyl amine
Column chromatography (alkali alumina, sherwood oil: ethyl acetate=drip washing in 10: 1) get yellow liquid.
1H NMR (C 6D 6, Me 4Si) δ 5.97 (t, J=6.9Hz, 1H), 6.25-6.30 (m, 2H), 6.32 (d, J=3.9Hz, 1H), 6.51 (d, J=4.2Hz, 1H), and 6.56-6.57 (m, 1H), 6.80-6.86 (m, 1H), 6.94-6.99 (m, 1H), 7.05 (d, J=9.3Hz, 1H), and 7.10-7.12 (m, 2H), 7.27-7.30 (m, 2H), 7.50 (d, J=7.2Hz, 1H). 13C NMR (C 6D 6) δ 99.35,111.76,114.11,118.01,119.56,120.83,121.60,125.34,126.16,127.01,129.07,131.46,132.12,133.36,137.32,142.35,162.82.HRMS (EI) calculated value C 19H 14N 2OS 318.0827, measured value 318.0819.
Synthesizing of embodiment 9:N-(3-indolizine base)-N-phenylbenzamaide
Figure A20061011799600181
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmolN-phenyl N-(2-propargyl)-benzamide, 2mL N,N-dimethylacetamide, 0.01mmolPdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI, 1.5mmol DBU, be warming up to 80 ℃ and stir 3h, be cooled to room temperature then, add the shrend reaction of going out, diatomite filtration, filtrate is used ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 10) get 129mg N-(3-indolizine base)-N-phenylbenzamaide, yield 83%.
N-(3-indolizine base)-N-phenylbenzamaide
Alkalescence alchlor column chromatography for separation (ethyl acetate: sherwood oil=1: 10) obtain bright green liquid.
1H NMR (CDCl 3, Me 4Si) δ 6.32 (d, J=4.2Hz, 1H), 6.53 (d, J=3.9Hz, 1H), 6.66-6.71 (m, 1H), 7.10-7.19 (m, 3H), 7.23-7.36 (m, 9H), 7.73 (d, J=6.9Hz, 1H). 13C NMR (CDCl 3) δ 98.44,111.40,112.85,117.16,119.44,120.02,121.59,124.74,126.08,127.15,127.78,129.01,130.45,130.57,135.66,141.13,171.13.HRMS (EI) calculated value C 21H 16N 2O 312.1263, measured value 312.1266.
Synthesizing of embodiment 10:N (3-indolizine base)-N-phenylcarbamic acid tert-butyl ester
In standard Schrenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmolN phenyl-N-(2-propargyl) t-butyl carbamate, 2mL N,N-dimethylacetamide, 0.01mmolPdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI, 1.5mmol DBU, be warming up to 80 ℃ and stir 6h, be cooled to room temperature then, add the shrend reaction of going out, diatomite filtration, filtrate is used ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 30) get 110mg N-(3 indolizine base)-N-phenylcarbamic acid tert-butyl ester, yield 72%.
N-(3-indolizine base)-N-phenyl amido t-butyl formate
Column chromatography (alkali alumina, ethyl acetate: sherwood oil :=1: 30) get little yellow liquid, 1H NMR (CDCl 3, Me 4Si) δ 1.38 (s, 9H), 6.43 (d, J=4.2Hz, 1H), 6.49-6.54 (m, 1H), 6.64-6.69 (m, 2H), 7.06-7.12 (m, 1H), 7.22-7.30 (m, 4H) 7.35 (d, J=8.7Hz, 1H), 7.71 (dd, J=6.9, J=0.9Hz, 1H). 13C NMR (CDCl 3) δ 27.95,81.56,97.87,110.52,110.77,116.67,119.29,120.32,121.56,124.09,125.27,128.62,130.18,141.85,153.75.HRMS (EI) calculated value C 19H 20N 2O 2308.1525, measured value 308.1519.
Synthesizing of embodiment 11:1-(3-indolizine base)-Cyclohexamide
Figure A20061011799600201
In standard Schlenk pipe, add 0.5mmol 2-bromopyridine, 0.5mmol1-(2-propargyl)-Cyclohexamide, 2mL N,N-dimethylacetamide, 0.01mmol PdCl under the room temperature nitrogen protection successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 3 hours, be cooled to room temperature then, add the shrend reaction of going out, ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates, column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 2), get 82 milligrams of colourless oil liquids, yield is 79%.
1-(3-indolizine base)-Cyclohexamide
Column chromatography (alkali alumina, ethyl acetate: sherwood oil :=1: 2) get colourless oil liquid. 1H NMR (CDCl 3, Me 4Si) δ 1.87 (s, 6H), 2.76 (d, J=4.5Hz, 2H), 3.68-3.79 (m, 2H), 6.41 (d, J=3.9Hz, 1H), and 6.49-6.54 (m, 1H), 6.57 (d, J=4.2Hz, 1H), 6.66 (ddd, J=9.0Hz, 6.3Hz, 1.2Hz, 1H), 7.34 (d, J=8.7Hz, 1H), 7.51-7.54 (m, 1H); 13C NMR (CDCl 3, Me 4Si) δ 23.50,29.34, and 29.77,37.23,53.80,97.49,107.88,110.24,116.48,119.22,121.01,124.28,130.13,176.38; HRMS (EI) calculated value C 14H 16N 2O 228.1263, measured value 228.1270.
Embodiment 12:3-[N-(3-indolizine base)-N-phenyl]-amino indolizine synthetic
Figure A20061011799600202
In standard Schrenk pipe, add 1.5mmol 2-bromopyridine, 0.5mmolN-phenyl-N under the room temperature nitrogen protection successively, N-two (2-propargyl) aniline, 3mL N,N-dimethylacetamide, 0.02mmol PdCl 2(PPh 3) 2, 1.0mmol cuprous chloride, 4.0mmol DBU, be warming up to 80 ℃ and stir 26h, be cooled to room temperature then, add the shrend reaction of going out, diatomite filtration, filtrate is used ethyl acetate extraction, anhydrous magnesium sulfate drying concentrates column chromatography for separation (alkali alumina, ethyl acetate: sherwood oil=drip washing in 1: 100) get 70mg 3-[N-(3-indolizine base)-N-phenyl]-amino indolizine, yield 43%.
N-(3-indolizine base)-N-phenyl-3-amido indolizine
Column chromatography (alkali alumina, ethyl acetate: sherwood oil :=1: 50) get white solid. 1H NMR (CDCl 3, Me 4Si) δ 6.33-6.36 (m, 2H), 6.41 (d, J=3.9Hz, 2H), 6.49 (td, J=6.6, J=1.2Hz, 2H), and 6.64-6.69 (m, 2H), 6.74 (d, J=3.9Hz, 2H), 6.82-6.87 (m, 1H), 7.09-7.16 (m, 2H), 7.36-7.39 (m, 2H), 7.82 (dd, J=6.9, J=0.9Hz, 2H). 13C NMR (CDCl 3) δ 97.75,109.67,110.65,114.23,116.71,119.50,120.25,121.14,123.74,129.42,130.28,146.74.HRMS (EI) calculated value C 22H 17N 3323.1422, measured value 323.1421.
Synthesizing of embodiment 13:3-phenoxy group indolizine
Under nitrogen protection, add 0.5mmol 2-bromopyridine, 0.5mmol 3-phenoxy group-1-propine and 2 milliliters of N,N-dimethylacetamide successively, stir to clarify under the room temperature to 25 milliliters of Schlenk reaction tubess.Add 0.01mmol PdCl then successively 2(PPh 3) 2, 0.05mmol CuI and 1.5mmol DBU, be warming up to 80 ℃, stirred 8 hours.The TLC detection reaction finishes, and adds entry to reaction solution, ethyl acetate extraction three times.Merge organic phase, anhydrous magnesium sulfate drying revolves to boil off and desolventizes.Product uses alkaline alchlor column chromatography for separation, and (ethyl acetate: sherwood oil=1: 100), get 63 milligrams of oyster liquid, yield is 60%.
3-phenoxy group indolizine
1H NMR (CDCl 3, Me 4Si) δ 6.39-6.45 (m, 3H), 6.55-6.61 (m, 1H), 6.93 (d, J=7.8Hz, 2H), 7.06 (t, J=7.5Hz, 1H), 7.23-7.35 (m, 3H), 7.65 (d, J=6.9Hz, 1H); 13C NMR (CDCl 3, Me 4Si) δ 96.06,100.39, and 110.18,115.42,115.58,119.33,119.83,122.96,126.93,129.73,132.98,157.82; Ultimate analysis C 14H 11NO: calculated value C, 80.36; H, 5.30; N, 6.69; O, 7.65 measured value C, 80.06; H, 5.36; N, 6.51.
Embodiment 14:N, N '-dimethyl-N, N '-two (3-indolizine base)-to the synthetic preparation of pentanoic
Under nitrogen protection, add 1.5mmol 2-bromopyridine, 0.5mmol N successively, N '-dimethyl-N, N '-dipropargyl-, stir to clarify under the room temperature to pentanoic and 3 milliliters of N,N-dimethylacetamide to 25 milliliters of Schlenk reaction tubess.Add 0.02mmol PdCl then successively 2(PPh 3) 2, 0.10mmol CuI and 3.0mmol DBU, be warming up to 80 ℃, stirred 20 hours.The TLC detection reaction finishes, and adds entry to reaction solution, ethyl acetate extraction three times.Merge organic phase, anhydrous magnesium sulfate drying revolves to boil off and desolventizes.Product uses alkaline alchlor column chromatography for separation, and (methylene dichloride: sherwood oil=2: 3), get 131 milligrams of green solid, total recovery is 72%.
Figure A20061011799600221
N, N '-dimethyl-N, N '-two (3-indolizine base)-to pentanoic
1H NMR (CDCl 3, Me 4Si) δ 3.28 (s, 6H), 6.41 (s, 8H), 6.54-6.64 (m, 4H), 7.34 (d, J=9.0Hz, 2H), 7.57 (d, J=6.9Hz, 2H); 13C NMR (CDCl 3, Me 4Si) δ 39.78,97.23, and 108.07,109.91,114.59,116.22,119.24,121.32,128.77,129.38,141.44; Ultimate analysis C 24H 22N 4: calculated value C, 78.66; H, 6.05; N, 15.29; Measured value C, 78.66; H, 5.86; N, 15.44.

Claims (7)

1, a kind of indolizine compound of 3-position replacement, it has following structural formula:
Wherein, R 1, R 2, R 3Or R 4=H, C 1-16Alkyl or aryl, perhaps R 1And R 2, R 2And R 3, R 3And R 4Between connect the benzo ring;
Y is C or N;
... .. is singly-bound or does not have key;
Z=NR 5R 6Perhaps OR 7Acyl group;
R 5Or R 6=H, molecular formula are R 8The acyl group of CO, R 9Aryl that replaces or heteroaryl, R 9The aryl sulfonyl, the C that replace 1-16Alkyl, benzyl, C 2-C 6Thiazolinyl, alkynyl, C 5-8Cycloalkyl; Perhaps R 5-R 6Between connect into ring in twos;
R 7Be C 1-16Alkyl, R 9Aryl that replaces or heteroaryl, benzyl, C 5-8Cycloalkyl, R 8The acyl group of CO;
R 8Be C 1-16Alkyl, C 1-6Alkoxyl group, R 9The aryl or heteroaryl, benzyl or the C that replace 5-8Cycloalkyl;
R 9Be H, C 1-16Alkyl, C 1-6Alkoxyl group, aryl, nitro, amino, ester group, acyl group or halogen, as F, Cl, Br or I;
Described aryl refers to phenyl, naphthyl, anthryl or fluorenyl; Heteroaryl refers to pyridyl, thienyl, furyl, imidazolyl, pyranyl, pyrimidyl, indyl, carbazyl, thiazolyl, quinolyl, isoquinolyl, indolizine base, benzothienyl, benzofuryl or benzothiazolyl;
Restricted condition is: work as R 1-R 4=H, R 5Or R 6=C 1-16Alkyl the time, R 6Or R 5≠ aryl; Work as R 1-R 4=H, R 5Or R 6=C 2-C 6Thiazolinyl the time, R 6Or R 5≠ aryl; Work as R 1-R 4=H, R 5And R 6≠ benzyl; R 3And R 4Between when being the benzo ring, R 5Or R 6=C 1-16Alkyl the time, R 6Or R 5≠ aryl; Work as R 1-R 4=H, R 5And R 6When not connecting into cycloalkyl.
2, the method for the indolizine compound that replaces of a kind of synthetic 3-position, it is characterized in that in organic solvent and room temperature to 130 ℃ under, molecular formula is Bromo heterogeneous ring compound and molecular formula be
Figure A2006101179960003C2
Terminal alkyne set out, in the presence of equivalent or excessive mineral alkali or organic bases, carried out catalyzed reaction 1～96 hour with the bimetallic catalytic system that transition-metal catalyst and mantoquita are formed; The mol ratio of described bromo heterogeneous ring compound, terminal alkyne, transition-metal catalyst, mantoquita, alkali is followed successively by: 1 :-1.5: 0.005-0.2: 0.01-2: 3-6;
Described mineral alkali is oxyhydroxide, carbonate, supercarbonate or the phosphoric acid salt mineral alkali of monovalence metal; Described organic bases is the organic amine compound that has lone-pair electron;
R wherein 1, R 2, R 3, R 4, Z, Y and ... .. but does not have the described restricted condition of claim 1 according to claim 1.
3, the method for the indolizine compound of synthetic 3-position replacement as claimed in claim 2 is characterized in that described transition-metal catalyst is Pd (PPh 3) 4, Pd (PPh 3) 2Cl 2Or Ni (PPh 3) 2Cl 2
4, the method for the indolizine compound of synthetic 3-position replacement as claimed in claim 2 is characterized in that described mantoquita is CuI, CuCl, CuBr, neutralized verdigris or fluoroform sulphonyl copper.
5, the method for the indolizine compound of synthetic 3-position replacement as claimed in claim 2 is characterized in that described mineral alkali is K 2CO 3, Na 2CO 3, NaHCO 3, NaOCOCH 3, KOH or Cs 2CO 3The described organic amine compound that has lone-pair electron is diethylamine, triethylamine, 1,8-diazabicylo [5.4.0]-7-hendecene, triethylene diamine, pyridine, piperidines or tetramethyleneimine.
6, the method for the indolizine compound of synthetic 3-position replacement as claimed in claim 1 or 2, it is characterized in that described organic solvent solvent is benzene,toluene,xylene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diethylamine, triethylamine, 1,4-is to the mixed solvent of oxygen six rings, acetonitrile dimethyl sulfoxide (DMSO), hexamethylphosphoramide or above-mentioned solvent.
7, the method for the indolizine compound that replaces of synthetic 3-as claimed in claim 1 or 2 position, it is characterized in that described reaction after, employing recrystallization, thin-layer chromatography, column chromatography or the vacuum distillation method of product purified and separated.
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* Cited by examiner, † Cited by third party
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CN101302227B (en) * 2008-07-09 2010-12-22 中国科学院上海有机化学研究所 Method for synthesizing 3,3'-purrocoline compounds
CN101486710B (en) * 2009-02-11 2011-04-06 中国科学院上海有机化学研究所 Method for synthesizing 3-halogenated indolizine compound
CN103588649A (en) * 2013-11-08 2014-02-19 昆明理工大学 Method for synthesizing arylamine methylacetylene
CN110872295A (en) * 2018-08-30 2020-03-10 浙江工业大学 Method for synthesizing imidazo [1,2-a ] indole compound
CN113429407A (en) * 2021-06-28 2021-09-24 河南师范大学 Simple synthesis method of 1-alkyl-3-aryl substituted indolizine compound

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GB2287706A (en) * 1994-03-21 1995-09-27 Fujisawa Pharmaceutical Co Indolizine derivatives
WO1998047507A1 (en) * 1997-04-24 1998-10-29 Shionogi & Co., Ltd. Method for the treatment of stroke using n-heterocyclic glyoxylamide compounds

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CN101302227B (en) * 2008-07-09 2010-12-22 中国科学院上海有机化学研究所 Method for synthesizing 3,3'-purrocoline compounds
CN101486710B (en) * 2009-02-11 2011-04-06 中国科学院上海有机化学研究所 Method for synthesizing 3-halogenated indolizine compound
CN103588649A (en) * 2013-11-08 2014-02-19 昆明理工大学 Method for synthesizing arylamine methylacetylene
CN110872295A (en) * 2018-08-30 2020-03-10 浙江工业大学 Method for synthesizing imidazo [1,2-a ] indole compound
CN113429407A (en) * 2021-06-28 2021-09-24 河南师范大学 Simple synthesis method of 1-alkyl-3-aryl substituted indolizine compound

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