CN101113150A - Method for synthesizing bicycle aza ring fluorescent or phosphorescent compound - Google Patents
Method for synthesizing bicycle aza ring fluorescent or phosphorescent compound Download PDFInfo
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- CN101113150A CN101113150A CNA2006100889410A CN200610088941A CN101113150A CN 101113150 A CN101113150 A CN 101113150A CN A2006100889410 A CNA2006100889410 A CN A2006100889410A CN 200610088941 A CN200610088941 A CN 200610088941A CN 101113150 A CN101113150 A CN 101113150A
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Abstract
The invention relates to a synthetic method of a dicyclic azacyclo fluorescence or phosphorescent compounds: a metal carbene compound with a dicyclic azacyclo structure skeleton is produced from a carbene compound and 2-pyrazoline-5-ketone through a cycloaddition reaction in an organic solvent, and cis- and trans- dicyclic azacyclo organic compounds are respectively prepared after oxidation and demetalization; wherein, the cis-dicyclic azacyclo compounds have strong fluorescence performance, which can be uses as a small molecule probe compound for the analysis and checking of protein and cell; trans-dicyclic azacyclo compound is a non-fluorescent compound and may has phosphorescence; the oxidant used is inorganic or organic oxidant, and the reaction solvent is polar or non-polar organic solvent. The invention is of simple operation, with material easy to be acquired, a few reaction steps, better efficiency and selectiveness than traditional method; in particularly, compared with traditional synthesis method, the invention can more easily synthesize asymmetrical dicyclic azocyclo bimane compound.
Description
Technical field
The present invention relates to a kind of synthetic method with azabicyclo cyclic cpds of character of fluorescing or phosphorescent character.
Technical background
The compound that has an azabicyclo ring structure suc as formula this class shown in the I is by people such as Kosower synthetic first (Kosower, E.M. when handling 3-methyl-4-alkyl-4-chloro-2-pyrazolin-5-one compound with highly basic; Pazhenchevsky, B.; Hershkowitz, H.J.Am.Chem.Soc.1978,102,4983-4993).Used method is the β-position CH of elder generation with methyl aceto acetate
3Alkylations such as Br generate 3-methyl-4-alkyl-2-pyrazolin-5-one with hydrazine reaction then, then with chlorine chlorination are carried out in the 4-position of this pyrazolone, take off HCl/N at last under alkaline condition
2Cyclisation generates this azabicyclo cyclic cpds.
According to the constructional feature of this compound, people such as Kosower are referred to as 9 with this compound, 10-dioxabimane (being called for short bimane).The azabicyclo cyclic cpds that wherein has cis syn-structure has small molecules probe (Mansoor, the S.E. that strong fluorescence can be used as analyzing and testing protein and cell; Farrens, D.L.Biochemistry 2004,43, and 9426-9438), the corresponding isomer dinitrogen heterogeneous ring compound of its trans anti-structure is the non-fluorescence of a class and the material that may have phosphorescence character.People such as Kosower have been developed synthetic method (Kosower, the E.M. of symmetrical bimane compd A and B thus; Zbaida, D.; Baud ' huin, M.; Marciano, D.; Goldberg, I.J.Am.Chem.Soc.1990,112,7305; Shalev, D.E.; Chiacchiera, S.M.; Radkowsky, A.E.; Kosower, E.M.J.Org.Chem.1996,61,1689; Kosower, E.M.; Ben-Shoshan, M.J.Org.Chem.1996,61,5871.), but this synthetic method efficient is not high under many circumstances.To use two kinds of chlorated pyrazolones in 4-position during with synthetic asymmetric bimane Compound C of Kosower method and D, building-up reactions may generate 6 kinds of bimane compound products, the unusual difficulty of separation and purification target product thus is lower during the synthetic symmetrical bimane compound of efficiency ratio.
(Fischer, E.O. since 1 964 years people such as Fischer have synthesized first carbene compound; Maasb l, A.Angew.Chem.Iht.Ed.1964,3,580), because the Fischer carbene compound is stable to empty G﹠W, reactive behavior is high, they are always as important organic synthesis reagent be widely used in organic synthesis (Barluenga, J.; Fern á ndez-Rodr í guez, M.A.; Aguilar, E.J.Organomet.Chem.2005,690,539.Barluenga, J.; Santamaria, J.; Tom á s, M.Chem.Rev.2004,104,2259.).The Fischer carbene compound has the multikey reactive center, can with the organic reagent generation successive reaction that contains a plurality of reactive groups, generate many toroidal molecules skeleton.This class skeleton structure utilize traditional method to be difficult to synthetic often or synthesis step more, efficient is lower.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of bicycle aza ring fluorescent or phosphorescent compound.
For achieving the above object, the present invention utilizes the Fischer carbene compound as synthon, generate metal carbene compound through successive addition-cyclization with the pyrazolone that contains N-H and C=N reactive center simultaneously with bicyclic nitrogen heterocycles skeleton, through the oxidation demetalization, obtained keeping the constant organic bimane compound of bicyclic nitrogen heterocycles skeleton structure then.By regulating the substituting group on the pyrazolone, the present invention can synthesize the various asymmetric bimane compound that is difficult to prepare by traditional method.
Technical scheme of the present invention is as follows:
The synthetic method of bicycle aza ring fluorescent provided by the invention or phosphorescent compound, the reaction as shown in the formula:
In the formula:
R is an alkyl;
R
1, R
2Be methyl, ethyl, propyl group, phenyl, methylene radical or hydrogen atom;
M is a VI group 4 transition metal element;
Reactions steps is:
A) with Fischer carbene compound (OC)
5M=C (OR) C ≡ CPh (R=Et or Me; M=Cr or W) 1 be synthon, replaced the 2-pyrazolin-5-one with raw material in 1: 1 in molar ratio or 3-pyrazolin-5-one 2 is dissolved in the organic solvent, under room temperature-70 ℃, reacted 10-180 minute, generate metal carbene compound with bicyclic nitrogen heterocycles structural framework through addition-cyclization;
B) under the ice bath temperature, the metal carbene compound that step a is obtained is dissolved in the organic solvent, and in molar ratio 1: 1-4 adds oxygenant, and reaction is 20-70 minute under room temperature, obtains trans respectively and bicyclic nitrogen heterocycles organic compound cis;
Described oxygenant is inorganic oxidizer or organic oxidizing agent;
Described solvent is one or more polarity or nonpolar inert solvent.
Described synthetic method, wherein, R is methyl or ethyl.
Described synthetic method, wherein, R
1, R
2Be methyl, ethyl, propyl group, phenyl or methylene radical.
Described synthetic method, wherein, the product that step a obtains carries out step b through weighing after brilliant knot or column chromatography carry out purifying again.
Described synthetic method, wherein, the product that step b obtains carries out purifying through heavy brilliant knot or column chromatography.
Described synthetic method, wherein, the solvent that is used for recrystallization purifying is selected methylene dichloride/Skellysolve A, ether/Skellysolve A, methylene dichloride/sherwood oil for use; The solvent of column chromatography purification is selected unmodified packed column for use, is leacheate with sherwood oil and methylene dichloride, sherwood oil and ether or methylene dichloride and ether.
Described synthetic method, wherein, the M in the Fischer Cabbeen synthon is chromium or tungsten.
Described synthetic method, wherein, inorganic oxidizer is a ceric ammonium nitrate; Organic oxidizing agent be between-chloroperoxybenzoic acid.
Described synthetic method, wherein, organic solvent is tetrahydrofuran (THF), ether, 1,4-dioxane, methylene dichloride, chloroform, hexane or benzene.
The present invention has the following advantages
1. raw material 2-pyrazolin-5-one is easy to get, and is synthetic by keto ester and hydrazine hydrate reaction;
2.Bimane the preparation condition gentleness of precursor compound 3 and 4 is separated and is purified easily.
3. oxidation demetalization reaction conditions gentleness, yield is therefrom waited until good;
4. reactions steps is few;
5, relatively prior synthesizing method can more easily synthesize asymmetric bimane compound.
Description of drawings
Fig. 1 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6a
-5The M dioxane solution);
Fig. 2 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6b
-5The M dioxane solution);
Fig. 3 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6c
-5The M dioxane solution);
Fig. 4 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6d
-5The M dioxane solution);
Fig. 5 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6e
-6The M dioxane solution);
Fig. 6 is fluorescence excitation and the emmission spectrum figure (1 * 10 of syn-Bimane 6f
-6The M dioxane solution).
Embodiment
The present invention is a synthon with Fischer carbene compound (1), replaces 2-pyrazolin-5-one (2) and generates carbene compound (3) and (4) with azabicyclo ring structure for raw material successive reaction through addition-cyclisation in organic solvent.Compound (3) and (4) generate the fluorescigenic compound (6) that has possible phosphorescent compound (5) of transconfiguration and have cis-structure respectively after oxygenant oxidation demetalization.The building-up reactions formula is as follows:
Wherein:
Compound (1) is a Fischer carbene compound synthon, and substituent R is an alkyl; M is a VI group 4 transition metal element.
Compound (2) is for replacing 2-pyrazolin-5-one, wherein R
1And R
2Be alkyl or hydrogen atom, wherein alkyl can be as methyl, ethyl, propyl group, phenyl, methylene radical.
Compound (3) and (4) are the Fischer carbene compounds that contains bicyclic nitrogen heterocycles skeleton and metal part.
Oxygenant is inorganic or organic oxidizing agent, as ceric ammonium nitrate (CAN) ,-chloroperoxybenzoic acid (m-CPMA) etc.
Reaction solvent is one or more polarity or nonpolar inert solvent; Its polar solvent can be tetrahydrofuran (THF), ether, 1, and 4-dioxane, methylene dichloride or chloroform etc., non-polar solvent can be hexane or benzene etc.
Help further to understand the present invention by following embodiment, but content of the present invention is not limited to this.Cabbeen synthon described in following examples is (CO)
5M=C (OR) C ≡ CPh, i.e. R=Et or Me, M=Cr or W.
Embodiment 1: bicyclic nitrogen heterocycles carbene compound 3a and 4a's is synthetic
Drop into Fischer carbene compound 1a (1.0mmol) in the 5ml reaction flask, 3-antazoline-5-ketone 2a (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 30min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3a yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 35.1%; Collecting blue color component 4a yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 23.4%.
Embodiment 2: bicyclic nitrogen heterocycles carbene compound 3b and 4b's is synthetic
Drop into Fischer carbene compound 1b (1.0mmol) in the 5ml reaction flask, 3-antazoline-5-ketone 2a (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 30min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3b yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 46.4%; Collecting blue color component 4b yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 23.0%,
Embodiment 3: bicyclic nitrogen heterocycles carbene compound 3c and 4c's is synthetic
Drop into Fischer carbene compound 1a (1.0mmol) in 5 ml reaction flasks, 3-propyl group-2-pyrazolin-5-one 2b (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 30min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3c yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 46.7%; Collecting blue color component 4c yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 16.0%.
Embodiment 4: bicyclic nitrogen heterocycles carbene compound 3d and 4d's is synthetic
Drop into Fischer carbene compound 1b (1.0mmol) in the 5ml reaction flask, 3-propyl group-2-pyrazolin-5-one 2b (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 20min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3d yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 53.0%; Collecting blue color component 4d yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 15.7%.
Embodiment 5: bicyclic nitrogen heterocycles carbene compound 4e's is synthetic
Drop into Fischer carbene compound 1a (1.0mmol) in the 10ml reaction flask, 3-phenyl-2-pyrazolin-5-one 2c (1.0mmol) adds 1,4-dioxane (dioxane) 6ml.Entire reaction is installed in 65 ℃ of oil baths and stirs 180min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting blue color component 4e yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 11.9%.
Embodiment 6: by the synthetic bicyclic nitrogen heterocycles carbene compound 4e of 3-phenyl-3-pyrazolin-5-one
Drop into Fischer carbene compound 1a (1.0mmol) in the 10ml reaction flask, 3-phenyl-3-pyrazolin-5-one 2g (1.0mmol) adds 1,4-dioxane (dioxane) 6ml.Entire reaction is installed in 65 ℃ of oil baths and stirs 180min, and reaction finishes the afterreaction mixture through silica gel column chromatography separating purification, and collecting blue color component 4e yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 10.3%.
Embodiment 7: bicyclic nitrogen heterocycles carbene compound 3f and 4f's is synthetic
Drop into Fischer carbene compound 1b (1.0mmol) in the 10ml reaction flask, 3-phenyl-2-pyrazolin-5-one 2c (1.0mmol) adds 1,4-dioxane (dioxane) 6ml.Entire reaction is installed in 65 ℃ of oil baths and stirs 110min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3f yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 6: 1) is 14.1%; Collecting blue color component 4f yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 9.7%.
Embodiment 8: bicyclic nitrogen heterocycles carbene compound 3g and 4g's is synthetic
In the 10ml reaction flask, drop into Fischer carbene compound 1a (1.0mmol), 3,4-dimethyl-2-pyrazolin-5-one 2d (1.0mmol) adds 1,4-dioxane (dioxane) 6ml.Entire reaction is installed in 65 ℃ of oil baths and stirs 20min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3g yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 30.0%; Collecting blue color component 4g yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 43.7%.
Embodiment 9: bicyclic nitrogen heterocycles carbene compound 3h and 4h's is synthetic
In the 10ml reaction flask, drop into Fischer carbene compound 1b (1.0mmol), 3,4-dimethyl-2-pyrazolin-5-one 2d (1.0mmol) adds 1,4-dioxane (dioxane) 6ml.Entire reaction is installed in 65 ℃ of oil baths and stirs 30min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting red component 3h yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 6: 1) is 44.0%; Collecting purple component 4h yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 33.6%.
Embodiment 10: bicyclic nitrogen heterocycles carbene compound 4i's is synthetic
In the 5ml reaction flask, drop into Fischer carbene compound 1a (1.0mmol), 3,4-trimethylene-2-pyrazolin-5-one 2e (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 60min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting blue color component 4i yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 24.1%.
Embodiment 11: bicyclic nitrogen heterocycles carbene compound 4j's is synthetic
In the 5ml reaction flask, drop into Fischer carbene compound 1b (1.0mmol), 3,4-trimethylene-2-pyrazolin-5-one 2e (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 60min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting blue color component 4j yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 33.5%.
Embodiment 12: bicyclic nitrogen heterocycles carbene compound 3k and 4k's is synthetic
In the 5ml reaction flask, drop into Fischer carbene compound 1a (1.0mmol), 3,4-tetramethylene-2-pyrazolin-5-one 2f (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 15min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3k yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 7.7%; Collecting blue color component 4k yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 24.2%.
Embodiment 13: bicyclic nitrogen heterocycles carbene compound 3l and 4l's is synthetic
In the 5ml reaction flask, drop into Fischer carbene compound 1b (1.0mmol), 3,4-tetramethylene-2-pyrazolin-5-one 2f (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 15min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting red component 3l yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 41.5%; Collecting purple component 4l yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 23.3%.
Embodiment 14: bicyclic nitrogen heterocycles carbene compound 3m and 4m's is synthetic
Drop into Fischer carbene compound 1c (1.0mmol) in the 5ml reaction flask, 3-antazoline-5-ketone 2a (1.0mmol) adds tetrahydrofuran (THF) (THF) 3ml.Entire reaction is installed in 50 ℃ of oil baths and stirs 25min, reaction finishes the afterreaction mixture can be through column chromatographic isolation and purification, chromatography column is a silicagel column, and collecting purple component 3m yield when elutriant when being sherwood oil (30～60 ℃)/methylene dichloride (v/v, 4: 1) is 41.2%; Collecting blue color component 4m yield when elutriant is a sherwood oil (30～60 ℃)/methylene dichloride (v/v, 2: 1) is 25.7%.
Embodiment 15: prepare anti-bimane 5a by carbene compound 3a or 3b
In the 10ml reaction flask, drop into carbene compound 3a (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 30min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 6: 1), collect component 5a, yield is 79.4%.Utilize same quadrat method, yield that can 88.5% by 3b (0.3mmol) makes 5a.
Embodiment 16: prepare anti-bimane 5b by carbene compound 3c or 3d
In the 10ml reaction flask, drop into carbene compound 3c (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 45min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 6: 1), collect component 5b, yield is 80.0%.Utilize same quadrat method, yield that can 92.9% by 3d (0.3mmol) makes 5b.
Embodiment 17: prepare anti-bimane 5c by carbene compound 3f
In the 10ml reaction flask, drop into carbene compound 3f (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 40min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 6: 1), collect component 5c, yield is 77.6%.
Embodiment 18: prepare anti-bimane 5d by carbene compound 3g or 3h
In the 10ml reaction flask, drop into carbene compound 3g (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 45min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 6: 1), collect component 5d, yield is 80.4%.Utilize same quadrat method, yield that can 87.6% by 3h (0.3mmol) makes 5d.
Embodiment 19: prepare anti-bimane 5e by carbene compound 3k or 3l
In the 10ml reaction flask, drop into carbene compound 3k (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath ,-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation is added drop-wise in the reaction unit, remove then and continue to stir 50min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, and chromatography column is a silicagel column, and elutriant is a methylene dichloride, collect component 5e, yield is 83.0%.Utilize same quadrat method, yield that can 85.2% by 3l (0.3mmol) makes 5e.
Embodiment 20: prepare syn-bimane 6a by carbene compound 4a or 4b
In the 10ml reaction flask, drop into carbene compound 4a (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 60min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6a, yield is 76.4%.Utilize same quadrat method, yield that can 85.6% by 4b (0.3mmol) makes 6a.Compound 6a is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.69) sees accompanying drawing 1.
Embodiment 21: prepare syn-bimane 6b by carbene compound 4c or 4d
In the 10ml reaction flask, drop into carbene compound 4c (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 40min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6b, yield is 73.5%.Utilize same quadrat method, yield that can 91.7% by 4d (0.3mmol) makes 6b.Compound 6b is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.72) sees accompanying drawing 2.
Embodiment 22: prepare syn-bimane 6c by carbene compound 4e or 4f
In the 10ml reaction flask, drop into carbene compound 4e (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, metachloroperbenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 45min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6c, yield is 87.9%.Utilize same quadrat method, yield that can 85.5% by 4f (0.3mmol) makes 6c.Compound 6c is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.37) sees accompanying drawing 2.
Embodiment 23: be that oxygenant prepares syn-bimane 6c by carbene compound 4e with the ceric ammonium nitrate
Carbene compound 4e (0.3mmol) is dissolved in the 10ml acetone and is chilled to 0 ℃ with ice-water bath.Ceric ammonium nitrate (0.9mmol) is dissolved in the 10ml acetone, under agitation is added drop-wise in the reaction flask, and it is complete that ice-water bath stirs the 20min afterreaction down.Behind diatomite filtration, concentrating under reduced pressure, mixture are through purification by silica gel column chromatography, and elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6c, and yield is 39.3%.
Embodiment 24: prepare syn-bimane 6d by carbene compound 4g or 4h
In the 10ml reaction flask, drop into carbene compound 4g (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 40min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6d, yield is 76.2%.Utilize same quadrat method, yield that can 83.4% by 4h (0.3mmol) makes 6d.Compound 6d is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.11) sees accompanying drawing 3.
Embodiment 25: prepare syn-bimane 6e by carbene compound 4i or 4j
In the 10ml reaction flask, drop into carbene compound 4i (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 30min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6e, yield is 86.2%.Utilize same quadrat method, yield that can 83.3% by 4j (0.3mmol) makes 6e.Compound 6e is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.10) sees accompanying drawing 4.
Embodiment 26: prepare syn-bimane 6f by carbene compound 4k or 4l
In the 10ml reaction flask, drop into carbene compound 4k (0.3mmol), be dissolved in the 3ml dichloromethane solvent, reaction unit is placed ice-water bath, between-chloroperoxybenzoic acid (m-CPBA) (1.2mmol) is dissolved in the 3ml dichloromethane solvent, under agitation be added drop-wise in the reaction unit, remove then and continue to stir 50min under the ice-water bath room temperature, reaction finishes the afterreaction mixture can be through column chromatography purification, chromatography column is a silicagel column, elutriant is methylene dichloride/ether (v/v, 10: 1), collect component 6f, yield is 64.9%.Utilize same quadrat method, yield that can 76.4% by 4l (0.3mmol) makes 6f.Compound 6f is 1, the fluorescence spectrum (φ in the 4-dioxane solution
F=0.17) sees accompanying drawing 5.
Table 1. bicyclic nitrogen heterocycles metal carbene compound 3 and 4 synthetic
a
| Embodiment | 1 | 2 | M | R 1，R 2 | Solvent | Temperature (℃) | Time (min) | Product produces b(％) | |
| 1 2 3 4 5 6 7 8 9 10 11 12 | 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b | 2a 2a 2b 2b 2c 2c 2d 2d 2e 2e 2f 2f | Cr W Cr W Cr W Cr W Cr W Cr W | H，Me H，Me H，n-Pr H，n-Pr H，Ph H，Ph CH 3，CH 3 CH 3，CH 3 -(CH 2) 3- -(CH 2) 3- -(CH 2) 4- -(CH 2) 4- | THF THF THF THF dioxane dioxane dioxane dioxane THF |
50 50 50 50 65 65 65 65 50 50 50 50 | 30 30 30 20 180 110 20 30 60 60 15 15 | 3a(35.1) 3b(46.4) 3c(46.7) 3d(53.0) - 3f(14.1) 3g(30.0) 3h(44.0) - - 3k(7.7) 3l(41.5) | 4a(23.4) 4b(23.0) 4c(16.0) 4d(15.7) 4e(11.9) 4f(9.7) 4g(43.7) 4h(33.6) 4i(24.1) 4j(33.5) 4k(24.2) 4l(23.3) |
aReaction conditions: metal carbene compound 1,1.0mmol; Pyrazoline-substituting ketone 2,1.0mmol; Solvent is THF, 3ml or dioxane, 6ml; 50 ℃ or 65 ℃ of temperature of reaction.
bProductive rate (data in the bracket) is the column chromatography for separation productive rate.
Table 2. is by the synthetic bimanes 5 and 6 of 3 and 4 oxidation demetalizations
a
| Embodiment | Metal carbene | M | R 1，R 2 | Product | Time (min) | Productive rate b (％) |
| 13 14 | 3a 3b 3c | Cr W Cr | H，Me H，Me H，n-Pr | 5a 5b | 30 40 45 | 79.4 88.5 80.0 |
| 15 16 17 18 19 20 21 22 23 | 3d 3f 3g 3h 3k 3l 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l | W W Cr W Cr W Cr W Cr W Cr W Cr W Cr W Cr W | H，n-Pr H，Ph Me，Me Me，Me -(CH 2) 4- -(CH 2) 4- H，Me H，Me H，n-Pr H，n-Pr H，Ph H，Ph Me，Me Me，Me -(CH 2) 3- -(CH 2) 3- -(CH 2) 4- -(CH 2) 4- | 5c 5d 5e 6a 6b 6c 6d 6e 6f | 40 40 45 30 50 35 60 50 40 60 45 40 40 30 30 45 50 60 | 92.9 77.6 80.4 87.6 83.0 85.2 76.4 85.6 73.5 91.7 87.9 85.5 76.2 83.4 86.2 83.3 64.9 76.4 |
aReaction conditions: metal carbene compound 3 or 4,0.3mmol; Between-chloroperoxybenzoic acid (m-CPBA), 1.2mmol; Methylene dichloride, 6ml; 0 ℃-rt of temperature of reaction.
bProductive rate (data in the bracket) is the column chromatography for separation productive rate.
Claims (9)
1. the synthetic method of bicycle aza ring fluorescent or phosphorescent compound, reaction as shown in the formula:
In the formula:
R is an alkyl;
R
1, R
2Be alkyl or hydrogen atom;
M is a VI group 4 transition metal element;
Reactions steps is:
A) with Fischer carbene compound (OC)
5M=C (OR) C ≡ CPh is a synthon, and wherein R is methyl or ethyl; Be dissolved in the organic solvent with replacing 2-pyrazolin-5-one or 3-pyrazolin-5-one in 1: 1 in molar ratio, and under room temperature-70 ℃, react 10-180 minute, have the metal carbene compound of bicyclic nitrogen heterocycles structural framework through addition-cyclization generation;
B) under the ice bath temperature, the metal carbene compound that step a is obtained is dissolved in the organic solvent, and in molar ratio 1: 1-4 adds oxygenant, and reaction is 20-70 minute under room temperature, obtains trans respectively and bicyclic nitrogen heterocycles organic compound cis;
Described oxygenant is inorganic oxidizer or organic oxidizing agent;
Described solvent is one or more polarity or nonpolar inert solvent.
2. synthetic method as claimed in claim 1, wherein,
3. synthetic method as claimed in claim 1, wherein, R
1, R
2Be methyl, ethyl, propyl group, phenyl or methylene radical.
4. synthetic method as claimed in claim 1, wherein, the product that step a obtains carries out step b through weighing after brilliant knot or column chromatography carry out purifying again.
5. synthetic method as claimed in claim 1, wherein, the product that step b obtains carries out purifying through heavy brilliant knot or column chromatography.
6. as claim 4 or 5 described synthetic methods, wherein, the solvent that is used for recrystallization purifying is selected methylene dichloride/Skellysolve A, ether/Skellysolve A, methylene dichloride/sherwood oil for use; The solvent of column chromatography purification is selected unmodified packed column for use, is leacheate with sherwood oil and methylene dichloride, sherwood oil and ether or methylene dichloride and ether.
7. synthetic method as claimed in claim 1, wherein, the M in the Fischer Cabbeen synthon is chromium or tungsten.
8. synthetic method as claimed in claim 1, wherein, inorganic oxidizer is a ceric ammonium nitrate; Organic oxidizing agent be between-chloroperoxybenzoic acid.
9. synthetic method as claimed in claim 1, wherein, organic solvent is tetrahydrofuran (THF), ether, 1,4-dioxane, methylene dichloride, chloroform, hexane or benzene.
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