CN108047267B - 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compound and synthetic method thereof - Google Patents
1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compound and synthetic method thereof Download PDFInfo
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Abstract
The invention discloses 1-aza-5-germyl-5-bromobicyclo [3.3.3] having the following structural formula]Undecane and 1-aza-5-germyl-5-hydrobicyclo [3.3.3]Undecane compounds and methods for their synthesis. 1-aza-5-germyl-5-bromobicyclo [3.3.3] of the invention]Undecane and 1-aza-5-germyl-5-hydrobicyclo [3.3.3]Undecane compounds can be used to synthesize structurally rich 1-aza-5-germano-5-alkylbicyclo [3.3.3]The undecane compound, which is stable in nature and can exist stably in the air, is an important raw material for synthesizing alkyl germanium metal reagents, and the raw materials are easily available.
Description
Technical Field
The invention belongs to the field of preparation of organic metal compounds and relates to synthesis of germanium-containing compounds, in particular to 1-aza-5-germyl-5-R bicyclo [3.3.3] undecane compounds and a synthesis method thereof, wherein R is bromine or hydrogen.
Background
In 1992, the Edwin Vedejs project group firstly reported the synthesis of 1-aza-5-stanna-5-chlorobicyclo [3.3.3] undecane compounds, and further utilized the synthesis to prepare 1-aza-5-stanna-5-alkylbicyclo [3.3.3] undecane compounds, which realizes Stille cross-Coupling reaction of such alkylmetal reagents and aryl halides (see: Edwin Vedejs et al. internal Coordination at Tin proteins selected Alkyl transfer in the Stille Coupling reaction. J.Am. chem. Soc.1992, 114, 6556-.
In 2013, the Stille reaction of secondary alkyl cage tin catalyzed by the Biscoe subject group is further expanded, the reaction condition is mild, the substrate range is wide, the spatial configuration is maintained, and the importance and the application value of the 1-aza-5-stanna-5-chlorobicyclo [3.3.3] undecane compound are further proved (see: Li L, Wang C Y, Huang R, et al. stereospecific Pd-catalyzed Stille cross-linking reactions of secondary alkyl amide and aryl halide. Nature Chemistry, 2013, 5 (7): 607 and 612).
Germanium has the natural advantage of no toxicity as an element in the same family as tin, and the germanium replaces the tin to synthesize a compound with a similar structure, so that the advantage of a nitrogen-doped all-carbon chain cage structure can be exerted, and the use of the tin with high toxicity can be avoided. In 1996, Masanio Kosugi issue group reported 1-aza-5-germano-5-chlorobicyclo [3.3.3] undecane compounds, and further utilized to prepare 1-aza-5-germano-5-arylbicyclo [3.3.3] undecane compounds, which achieved Ge-Stille cross-coupling reaction of such aryl metal reagents with aryl halides (see: Masanio Kosugi et al Palladium-catalyzed reaction of 1-aza-5-germa-5-organobicylo [3.3.3] uncancewith aryl bromide. journal of Organometallic Chemistry 508(1996) 255-one 257).
However, after this document, no other document has reported the extended use of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compounds. Two reasons may be suspected: firstly, the literature does not report a specific method for synthesizing the 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compound, which cannot be repeated by a later person; secondly, in view of the property difference between the metal elements germanium and tin, the reactivity of the 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compound is weaker than that of the 1-aza-5-stannyl-5-chlorobicyclo [3.3.3] undecane compound, and the low activity limits the further development of the compound.
Disclosure of Invention
In view of the above, the present invention aims to improve the reactivity of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compounds, and to provide 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compounds and a process for producing the same.
To this end, in one aspect, the present invention provides a 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compound having the structure shown by the following formula:
in another aspect, the present invention provides a process for preparing a 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compound, the process comprising the steps of:
c) preparation of 1-aza-5-gera-5-alkylbicyclo [3.3.3] undecane: reacting 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane with an alkyl Grignard reagent in a solvent at room temperature for 4-6 hours under an inert atmosphere, and quenching the reaction to obtain 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dropwise adding liquid bromine into the 1-aza-5-germyl-5-alkyl bicyclo [3.3.3] undecane obtained in the step c) in a solvent to obtain a white solid product; and, optionally
e) Preparation of 1-aza-5-geraza-5-hydrobicyclo [3.3.3] undecane: under inert atmosphere, adding a reducing agent into the 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane obtained in the step d) in a solvent, and reacting for 1-2 hours at room temperature to obtain the product 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane.
The 1-aza-5-gerza-5-bromo (hydro) bicyclo [3.3.3] undecane can be used for synthesizing a 1-aza-5-gerza-5-alkyl bicyclo [3.3.3] undecane compound with a rich structure, has stable property, can stably exist in the air, is easy to obtain raw materials, and is an important raw material for synthesizing alkyl germanium metal reagents.
Drawings
FIG. 1 is a chart of the NMR spectrum of a 1-aza-5-geraza-5-bromobicyclo [3.3.3] undecane compound prepared according to example 1 of the present invention;
FIG. 2 is a chart of the carbon nuclear magnetic resonance spectrum of a 1-aza-5-geraza-5-bromobicyclo [3.3.3] undecane compound prepared according to example 1 of the invention;
FIG. 3 is a chart of the NMR spectrum of a 1-aza-5-geraza-5-hydrobicyclo [3.3.3] undecane compound prepared according to example 2 of the invention; and
FIG. 4 is a chart of the carbon nuclear magnetic resonance spectrum of a 1-aza-5-geraza-5-hydrobicyclo [3.3.3] undecane compound prepared according to example 2 of the invention;
Detailed Description
1-aza-5-stanna-5-R bicyclo [3.3.3] undecane compounds (wherein R is a substituent) have outstanding neutral properties in the field of cross coupling reaction, and are very distinctive synthons. However, the inventors of the present invention have found that, in view of the difference in properties between germanium and tin, which are metal elements, the reactivity of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compounds is weaker than that of 1-aza-5-stannyl-5-chlorobicyclo [3.3.3] undecane compounds, and the low activity limits the further development of the compounds. Therefore, the present inventors have intensively studied to design and synthesize a 1-aza-5-germyl-5-Rbicyclo [3.3.3] undecane compound (wherein R is bromine or hydrogen).
To this end, in a first aspect, the present invention provides a 1-aza-5-germyl-5-rbicyclo [3.3.3] undecane compound, wherein R is bromo or hydrogen, and which has the structure shown below:
thus, the 1-aza-5-germyl-5-Rbicyclo [3.3.3] undecane compounds of the invention (wherein R is bromo or hydrogen) are also referred to as 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compounds.
The 1-aza-5-germyl-5-bromo (hydro) bicyclo [3.3.3] undecane compound synthesized by the method can replace a 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane compound, can improve the reaction activity of the compound, and has very important practical value.
For example, as shown in the following formula, a 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane compound can react with a commercially available alkyl grignard reagent and an easily prepared alkyl zinc reagent under extremely mild conditions to realize the construction of a carbon-germanium bond. The prepared 1-aza-5-germyl-5-alkyl bicyclo [3.3.3] undecane compounds are metal reagents with excellent nucleophilic activity, are easy to separate and are stable to humidity and air.
The 1-aza-5-germyl-5-bromobicyclo [3.3.3] obtained by the preparation method of the invention]The undecane compound was subjected to hydrogen, carbon nuclear magnetic test, in which deuterated reagent used was deuterated chloroform (CDCl)3). The test results were as follows:
1H NMR(400MHz，CDCl3)2.63(t，6H)，1.79-1.85(m，6H)，1.55(t， 6H).
13C NMR(101MHz，CDCl3)54.93，22.88，21.25。
the 1-aza-5-germyl-5-hydrobicyclo [3.3.3] obtained by the preparation method of the invention]The undecane compound was subjected to hydrogen, carbon nuclear magnetic test, in which deuterated reagent used was deuterated benzene (C)6D6). The test results were as follows:
1H NMR(400MHz，C6D6)4.95(s，1H)，2.13(t，6H)，1.35-1.39(m，6H)， 0.88(t，6H).
13C NMR(101MHz，C6D6)53.54，22.75，11.19。
in another aspect, the invention provides a process for preparing a 1-aza-5-germyl-5-Rbicyclo [3.3.3] undecane compound, wherein R is bromo or hydrogen.
In the case where R is bromine, the process for preparing 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane compounds comprises the steps of:
c) preparation of 1-aza-5-gera-5-alkylbicyclo [3.3.3] undecane: reacting 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane with an alkyl Grignard reagent in a solvent at room temperature for 4-6 hours under an inert atmosphere, and quenching the reaction to obtain 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane; and
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dropwise adding liquid bromine into the solvent by using the 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane obtained in the step c) to obtain a white solid product.
In the case where R is hydrogen, the process for preparing 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane compounds comprises the steps of:
c) preparation of 1-aza-5-gera-5-alkylbicyclo [3.3.3] undecane: reacting 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane with an alkyl Grignard reagent in a solvent at room temperature for 4-6 hours under an inert atmosphere, and quenching the reaction to obtain 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dropwise adding liquid bromine to the 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane obtained in the above step c) in a solvent to obtain a white solid product, and
e) preparation of 1-aza-5-geraza-5-hydrobicyclo [3.3.3] undecane: under inert atmosphere, adding a reducing agent into the 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane obtained in the step d) in a solvent, and reacting for 1-2 hours at room temperature to obtain the product 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane.
In the present invention, the reducing agent used may be lithium aluminum hydride or the like.
In the present invention, the alkyl group in the term "alkyl grignard reagent" may be a substituted or unsubstituted alkyl group, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, benzyl, and the like.
In the present invention, the alkyl group in the term "1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane" may be a substituted or unsubstituted alkyl group including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, benzyl, and the like.
In the present invention, 1-aza-5-geraza-5-chlorobicyclo [3.3.3] undecane used as a starting material may be commercially available or may be prepared by a method comprising the steps of:
a) preparation of zirconocene hydrochloride: under inert atmosphere, stirring zirconocene dichloride and lithium aluminum hydride in a solvent at room temperature for 3-4 hours, and separating to obtain white solid zirconocene hydrochloride; and
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: stirring triallylamine compounds and the zirconocene hydrochloride obtained in the step b) in a solvent for 1-2 hours at room temperature under inert atmosphere until the solution is clear, then slowly dropwise adding germanium tetrachloride under the protection of inert gas, and then placing the reaction solution at 60-80 ℃ for reacting for 8-12 hours to obtain the 1-aza-5-gerdoped-5-chlorobicyclo [3.3.3] undecane.
In the above step b), the reaction solution is then left to react at 60 to 80 ℃ which is important for obtaining the desired product 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane. During the course of the investigation, the inventors found that if the reaction temperature is changed from 60 ℃ to room temperature, the desired reaction product cannot be obtained.
Thus, in one embodiment of the process of the present invention for preparing 1-aza-5-geraza-5-bromo (hydro) bicyclo [3.3.3] undecane compounds, there is provided a preparation process comprising the steps of:
a) preparation of zirconocene hydrochloride: under inert atmosphere, stirring zirconocene dichloride and lithium aluminum hydride in a solvent at room temperature for 3-4 hours, and separating to obtain white solid zirconocene hydrochloride;
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: stirring triallylamine compounds and zirconocene hydrochloride in a solvent for 1-2 hours at room temperature under inert atmosphere until the solution is clear, slowly dropwise adding germanium tetrachloride under the protection of inert gas, reacting the reaction solution at 60-80 ℃ for 8-12 hours after dropwise adding, cooling the reaction solution to room temperature, adding the solvent to separate out zirconocene dichloride, filtering, and drying the filtrate to obtain a crude product;
c) preparation of 1-aza-5-gera-5-benzylbicyclo [3.3.3] undecane: reacting the crude product obtained in the step b) with benzylmagnesium chloride in a solvent at room temperature for 4-6 hours under an inert atmosphere, adding a saturated solution of ammonium chloride to quench the reaction, extracting with the solvent, separating an organic phase, drying and separating to obtain 1-aza-5-germyl-5-benzylbicyclo [3.3.3] undecane;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dropwise adding liquid bromine into the 1-aza-5-germyl-5-benzylbicyclo [3.3.3] undecane obtained in the step c) in a solvent in the air until the liquid bromine is not faded any more and is completely precipitated, and filtering to obtain a white solid, namely the obtained product; and
e) alternatively, 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane is prepared: under inert atmosphere, adding lithium aluminum hydride into the 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane obtained in the step d) in a solvent, reacting for 1-2 hours at room temperature, filtering reaction liquid, spin-drying filtrate, washing the filtrate with the solvent to remove insoluble substances, and drying washing liquid to obtain the product 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane.
The solvent used in step a) of the present invention is one of tetrahydrofuran, toluene, benzene and diethyl ether.
The solvent used in the step b) of the present invention is one selected from tetrahydrofuran, dichloromethane, and n-hexane.
The solvent used in step c) of the present invention is one selected from tetrahydrofuran, dichloromethane, ethyl acetate, and n-hexane.
The solvent used in step d) of the present invention is one of carbon tetrachloride, toluene and acetone.
The solvent used in step e) of the present invention is one selected from tetrahydrofuran, dichloromethane, ethyl acetate, and n-hexane.
In step a) of the present invention, the molar ratio of zirconocene dichloride to lithium aluminum hydride is 3.0-4.5: 1, preferably 3.0-3.5: 1, more preferably 3.0-3.2: 1.
In step a) of the present invention, the amount of the solvent added is controlled to be optimal for the zirconocene dichloride to be just completely dissolved.
In step b), the molar ratio of the zirconocene hydrochloride to the triallylamine compound is 3.1-3.7: 1, preferably 3.1-3.5: 1, and more preferably 3.1-3.3: 1.
In step b) of the present invention, the molar ratio of germanium tetrachloride to triallylamine compound is 1.1-2.5: 1, preferably 1.1-2.0: 1, and more preferably 1.1-1.4: 1.
In the present invention, the term "triallylamine compounds" may include, in addition to triallylamine, other types of triallylamine compounds, such as triallylamine having the structure shown by the following formula:
In step c) of the present invention, the molar ratio of benzylmagnesium chloride to 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane is 2.0-5.0: 1, preferably 3.0-4.5: 1, more preferably 3.0-4.0: 1.
In step d) of the present invention, the liquid bromine is added at a relatively slow rate, mainly because if the liquid bromine is added too fast, which results in excess liquid bromine, the resulting product needs to be further purified, and the yield is reduced, preferably at a rate of one drop per second. The liquid bromine fades while the solution is added until the last drop of liquid bromine is added, the solution turns yellow and does not fade, and the phenomenon is indicated as the end of the reaction.
In step e) of the present invention, the molar ratio of the 1-aza-5-gerza-5-bromobicyclo [3.3.3] undecane to the lithium aluminum hydride is 0.5-2.0: 1, preferably 1.0-2.0: 1, more preferably 1.0-1.5: 1; the filtrate is washed by the solvent to remove insoluble substances, and the washing can be repeated for two to three times to completely remove impurities.
The preparation process of the present invention is preferably carried out in a Schlenk flask, so that the inert atmosphere required in the reaction can be conveniently controlled. The inert atmosphere used in the present invention is not particularly limited, and may be a nitrogen atmosphere, an argon atmosphere, or the like.
The preparation process of the present invention is further specifically described below with reference to specific examples, but these examples are not intended to limit the scope of the present invention, which is defined by the claims appended hereto.
Example 1
Preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane
a) Preparation of zirconocene hydrochloride: weighing 31mmol of zirconocene dichloride (chemical industry Co., Ltd., Beijing Huawei Ruiki Co., Ltd.) in a Schlenk bottle, charging argon on a vacuum line for three times, adding 70mL of anhydrous tetrahydrofuran into the argon until the solid is just completely dissolved, dissolving 10mmol of lithium aluminum hydride (Tishiei chemical industry Co., Ltd.) in the anhydrous tetrahydrofuran solvent, slowly adding the mixture into the Schlenk bottle in an inert gas atmosphere, stirring the mixture at room temperature for 3.5 hours after the dropwise addition is finished, and performing suction filtration separation to obtain white solid zirconocene hydrochloride, wherein the yield is 85%;
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: weighing 27mmol of zirconocene hydrochloride in a Schlenk bottle, filling argon on a vacuum line for three times, adding 20mL of dichloromethane, dropwise adding 8.2mmol of triallylamine (Tishhei chemical industry development Co., Ltd.) into the Schlenk bottle under inert atmosphere, stirring at room temperature for 1-2 hours until the solution is clear, slowly dropwise adding 9.84mmol of germanium tetrachloride (Alassarsa chemical Co., Ltd.) under inert gas protection, placing the reaction solution at 60 ℃ for reaction for 12 hours after dropwise adding is finished, cooling the reaction solution to room temperature after the reaction is finished, adding 60mL of n-hexane into the reaction solution to separate out zirconocene dichloride, filtering the zirconocene dichloride, and spin-drying the filtrate to obtain a crude product, wherein the yield of the crude product is 50%;
c) preparation of 1-aza-5-germyl-5-benzylbicyclo [3.3.3]Undecane: 1-aza-5-germyl-5-chlorobicyclo [3.3.3] is weighed into a Schlenk bottle]10mmol of undecane, charging argon three times on a vacuum line, and adding 25mL of anhydrous tetrahydrofuran under inert atmosphere to make 1-aza-5-germyl-5-chlorobicyclo [ 3.3.3%]Completely dissolving undecane, adding 35mmol of benzyl magnesium chloride, reacting at room temperature for 4-6 hr, adding saturated solution of ammonium chloride to quench the reaction, extracting with 50mL of n-hexane, separating organic phase, drying, spin drying,passing through silica gel column with n-hexane (R)f0.8) to give 1-aza-5-germano-5-benzylbicyclo [ 3.3.3)]The yield of the pure product of the undecane is 90 percent;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3]Undecane: in air, the 1-aza-5-germyl-5-benzylbicyclo [3.3.3]4mmol of undecane is dissolved in 5mL of carbon tetrachloride, liquid bromine is added dropwise until the liquid bromine does not fade any more and the precipitation is completely separated out, and the white solid is the obtained product after suction filtration, wherein the yield is 95%. FIGS. 1-2 are respectively views of 1-aza-5-germyl-5-bromobicyclo [3.3.3] prepared according to example 1 of the invention]Hydrogen and carbon nuclear magnetic resonance spectrum diagram of undecane, wherein the deuterated reagent used is deuterated chloroform (CDCl)3)。
1H NMR(400MHz，CDCl3)2.63(t，6H)，1.79-1.85(m，6H)，1.55(t， 6H).
13C NMR(101MHz，CDCl3)54.93，22.88，21.25.
Example 2
Preparation of 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane
a) Preparation of zirconocene hydrochloride: weighing 31mmol of zirconocene dichloride (chemical industry Co., Ltd., Beijing Huawei Ruiki Co., Ltd.) in a Schlenk bottle, charging argon on a vacuum line for three times, adding 70mL of anhydrous tetrahydrofuran into the argon until the solid is just completely dissolved, dissolving 10mmol of lithium aluminum hydride (Tishiei chemical industry Co., Ltd.) in the anhydrous tetrahydrofuran solvent, slowly adding the mixture into the Schlenk bottle in an inert gas atmosphere, stirring the mixture at room temperature for 3.5 hours after the dropwise addition is finished, and performing suction filtration separation to obtain white solid zirconocene hydrochloride, wherein the yield is 85%;
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: weighing 27mmol of zirconocene hydrochloride in a Schlenk bottle, filling argon on a vacuum line for three times, adding 20mL of dichloromethane, dropwise adding 8.2mmol of triallylamine (Tishieiyi chemical industry development Co., Ltd.) into the Schlenk bottle under inert atmosphere, stirring at room temperature for 1-2 hours until the solution is clear, slowly dropwise adding 9.84mmol of germanium tetrachloride (Alfa Sasa chemical Co., Ltd.) under inert gas protection, placing the reaction solution in an oil bath kettle at 60 ℃ for reaction for 12 hours after dropwise adding is finished, cooling the reaction solution to room temperature after the reaction is finished, adding 60mL of normal hexane into the reaction solution to separate out zirconocene dichloride, filtering the zirconocene dichloride, and spin-drying the filtrate to obtain a crude product, wherein the next reaction is directly carried out without further purification, and the yield of the crude product is 50%;
c) preparation of 1-aza-5-germyl-5-benzylbicyclo [3.3.3]Undecane: 1-aza-5-germyl-5-chlorobicyclo [3.3.3] is weighed into a Schlenk bottle]10mmol of undecane, charging argon three times on a vacuum line, and adding 25mL of anhydrous tetrahydrofuran under inert atmosphere to make 1-aza-5-germyl-5-chlorobicyclo [ 3.3.3%]Dissolving undecane completely, adding 35mmol of benzyl magnesium chloride, reacting at room temperature for 4-6 hr, adding saturated solution of ammonium chloride, quenching, extracting with 50mL n-hexane, separating organic phase, drying, and passing through silica gel column (R) with n-hexanef0.8) to give 1-aza-5-germano-5-benzylbicyclo [ 3.3.3)]The yield of the pure product of the undecane is 90 percent;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dissolving 4mmol of 1-aza-5-germanium hetero-5-benzyl bicyclo [3.3.3] undecane in 5mL of carbon tetrachloride in the air, dropwise adding liquid bromine until the liquid bromine is not faded any more and the precipitate is completely separated out, and performing suction filtration to obtain a white solid, namely the obtained product, wherein the yield is 95%.
e) Preparation of 1-aza-5-germyl-5-hydrobicyclo [3.3.3]Undecane: 1-aza-5-germyl-5-bromobicyclo [3.3.3] is weighed into a Schlenk bottle]1mmol of undecane, charging argon on a vacuum line for three times, adding solvent anhydrous tetrahydrofuran in inert atmosphere, adding 1mmol of lithium aluminum hydride in inert atmosphere, reacting at room temperature for 1 hour, filtering the reaction solution, spin-drying the filtrate, washing the filtrate with n-hexane to remove insoluble substances, repeating for two or three times to completely remove impurities, and spin-drying the washing solution to obtain the product 1-aza-5-germyl-5-hydrobicyclo [3.3.3]Undecane, yield 90%. FIGS. 3 to 4 are views of 1-aza-5-gera-5-hydrobicyclo [3.3.3] respectively prepared according to example 1 of the invention]Hydrogen and carbon nuclear magnetic resonance spectrum diagram of undecane, wherein the deuterated reagent used is deuterated benzene (C)6D6)。
1H NMR(400MHz，C6D6)4.95(s，1H)，2.13(t，6H)，1.35-1.39(m，6H)， 0.88(t，6H).
13C NMR(101MHz，C6D6)53.54，22.75，11.19.
Example 3
Preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane (influence of changing charge ratio on yield)
a) Preparation of zirconocene hydrochloride: weighing 35mmol of zirconocene dichloride (chemical Co., Ltd., Beijing Huawei Ruiki Co., Ltd.), filling argon on a vacuum line for three times, adding 70mL of anhydrous tetrahydrofuran into the argon until the solid is completely dissolved, dissolving 10mmol of lithium aluminum hydride (Tishiei chemical Co., Ltd.) into the solvent anhydrous tetrahydrofuran, slowly adding the mixture into a Schlenk bottle under an inert gas atmosphere, and after the dropwise addition, placing the reaction at room temperature and stirring for 3.5 hours. Compared with the optimal feeding ratio, the method has the advantages that the molar ratio of the zirconocene dichloride to the lithium aluminum hydride is increased to 3.5: 1, so that the suction filtration is difficult, and the yield of the separated zirconocene hydrochloride is only 70%;
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: weighing 27mmol of zirconocene hydrochloride in a Schlenk bottle, filling argon on a vacuum line for three times, adding 20mL of dichloromethane, dropwise adding 9mmol of triallylamine (Chishieiyi chemical development Co., Ltd.) in the Schlenk bottle under inert atmosphere, stirring at room temperature for 1-2 hours until the solution is clear, slowly dropwise adding 9mmol of germanium tetrachloride (Alfa Sasa chemical Co., Ltd.) under inert gas protection, placing the reaction solution at 60 ℃ for reaction for 12 hours after dropwise adding, cooling the reaction solution to room temperature after the reaction is finished, adding 60mL of n-hexane into the reaction solution to separate out zirconocene dichloride, filtering the zirconocene dichloride, and spin-drying the filtrate to obtain a crude product. Compared with the optimal feeding ratio, the molar ratio of the zirconocene hydrochloride to the triallylamine is reduced to 3.0: 1, the molar ratio of the germanium tetrachloride to the triallylamine is reduced to 1: 1, the triallylamine can not be completely reacted, and the yield of the crude product is only 30%;
c) preparation of 1-aza-5-germyl-5-benzylbicyclo [3.3.3]Undecane: 1-aza-5-germyl-5-chlorobicyclo [3.3.3] is weighed into a Schlenk bottle]10mmol of undecane inArgon is charged three times on a vacuum line, and under the inert atmosphere, 25mL of anhydrous tetrahydrofuran is added to ensure that the 1-aza-5-germanium hetero-5-chlorobicyclo [3.3.3]Dissolving undecane completely, adding benzyl magnesium chloride 25mmol, reacting at room temperature for 4-6 hr, adding saturated solution of ammonium chloride, quenching, extracting with 50mL n-hexane, separating organic phase, drying, and passing through silica gel column (R) with n-hexanef0.8) to give 1-aza-5-germano-5-benzylbicyclo [ 3.3.3)]Pure product of undecane. Reduced benzylmagnesium chloride and 1-aza-5-germyl-5-chlorobicyclo [3.3.3] compared to optimum charge ratios]A molar ratio of undecane of 2.5: 1 results in 1-aza-5-germyl-5-chlorobicyclo [3.3.3]The undecane reaction is incomplete, and the yield is only 70%;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dissolving 4mmol of 1-aza-5-germyl-5-benzyl bicyclo [3.3.3] undecane in 5mL of carbon tetrachloride in air, dropwise adding liquid bromine until the liquid bromine is not faded any more and the precipitate is completely separated out, and performing suction filtration to obtain a white solid, namely the obtained product. If the liquid bromine is added too quickly, resulting in excess liquid bromine, the product is further purified and the yield is reduced to 75%.
Example 4
Preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane (varying the effect of critical reaction temperature on yield)
a) Preparation of zirconocene hydrochloride: weighing 31mmol of zirconocene dichloride (chemical industry Co., Ltd., Beijing Huawei Ruiki Co., Ltd.) in a Schlenk bottle, charging argon on a vacuum line for three times, adding 70mL of anhydrous tetrahydrofuran into the argon until the solid is just completely dissolved, dissolving 10mmol of lithium aluminum hydride (Tishiei chemical industry Co., Ltd.) in the anhydrous tetrahydrofuran solvent, slowly adding the mixture into the Schlenk bottle in an inert gas atmosphere, stirring the mixture at room temperature for 3.5 hours after the dropwise addition is finished, and performing suction filtration separation to obtain white solid zirconocene hydrochloride, wherein the yield is 85%;
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: 27mmol of zirconocene hydrochloride is weighed in a Schlenk bottle, argon is filled for three times on a vacuum line, 20mL of dichloromethane is added into the bottle, 8.2mmol of triallylamine (Tishcheng chemical development Co., Ltd.) is added into the bottle dropwise under inert atmosphere, the solution is stirred for 1-2 hours at room temperature until the solution is clear, 9.84mmol of germanium tetrachloride (Alassa chemical Co., Ltd.) is slowly added dropwise under inert gas protection, the reaction temperature is changed from 60 ℃ to room temperature after the dropwise addition is finished, the reaction is carried out for 12 hours, after the reaction is finished, 60mL of n-hexane is added into the bottle to separate out the zirconocene dichloride, the zirconocene dichloride is filtered out, the filtrate is dried in a spinning mode, and the desired product 1-aza-5-germania-5-chlorobicyclo [3.3.3] undecane is not produced.
Example 5
Possible preparation of other types of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecanes
a) Preparation of zirconocene hydrochloride: weighing 31mmol of zirconocene dichloride (chemical industry Co., Ltd., Beijing Huawei Ruiki Co., Ltd.) in a Schlenk bottle, charging argon on a vacuum line for three times, adding 70mL of anhydrous tetrahydrofuran into the argon until the solid is just completely dissolved, dissolving 10mmol of lithium aluminum hydride (Tishiei chemical industry Co., Ltd.) in the anhydrous tetrahydrofuran solvent, slowly adding the mixture into the Schlenk bottle in an inert gas atmosphere, stirring the mixture at room temperature for 3.5 hours after the dropwise addition is finished, and performing suction filtration separation to obtain white solid zirconocene hydrochloride, wherein the yield is 85%;
b) preparation of other 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecanes: weighing 27mmol of zirconocene hydrochloride in a Schlenk bottle, filling argon on a vacuum line for three times, adding 20mL of dichloromethane, dropwise adding 8.2mmol of other triallylamine compounds into the Schlenk bottle under inert atmosphere, stirring for 1-2 hours at room temperature until the solution is clear, slowly dropwise adding 9.84mmol of germanium tetrachloride (Alassa chemical Co., Ltd.) under inert gas protection, placing the reaction solution at 60 ℃ for reaction for 12 hours after dropwise adding, cooling the reaction solution to room temperature after the reaction is finished, adding 60mL of n-hexane into the reaction solution to separate out the zirconocene dichloride, filtering the zirconocene dichloride, and spin-drying the filtrate to obtain a crude product, wherein the crude product is not required to be further purified and is directly subjected to the next reaction;
wherein other types of triallylamine compounds are represented by the following formula or other similar structures:
c) preparation of other 1-aza-5-germyl-5-benzylbicyclo [3.3.3] undecanes:
weighing 10mmol of other 1-aza-5-germania-5-chlorobicyclo [3.3.3] undecane compounds in a Schlenk bottle, filling argon on a vacuum line for three times, adding 25mL of anhydrous tetrahydrofuran under an inert atmosphere to completely dissolve other 1-aza-5-germania-5-chlorobicyclo [3.3.3] undecane compounds, adding 35mmol of benzyl magnesium chloride, reacting at room temperature for 4-6 hours after the addition is finished, adding a saturated solution of ammonium chloride to quench the reaction, extracting with 50mL of n-hexane, separating an organic phase, drying, spin-drying, and separating with the n-hexane to obtain other 1-aza-5-germania-5-benzylbicyclo [3.3.3] undecane compound pure products;
d) preparation of other 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecanes: dissolving 4mmol of other 1-aza-5-germanium hetero-5-benzyl bicyclo [3.3.3] undecane compounds in 5mL of carbon tetrachloride in the air, dropwise adding liquid bromine until the liquid bromine does not fade and is completely precipitated, and performing suction filtration to obtain a solid, namely the obtained product.
e) Preparation of other 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecanes: weighing 1mmol of other 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane compounds in a Schlenk bottle, charging argon on a vacuum line for three times, adding solvent anhydrous tetrahydrofuran in an inert atmosphere, adding 1mmol of lithium aluminum hydride in the inert atmosphere, reacting for 1 hour at room temperature, filtering reaction liquid, spin-drying filtrate, washing the filtrate with n-hexane for two or three times to remove insoluble substances, repeatedly drying the washing liquid for completely removing impurities, and spin-drying the washing liquid to obtain other 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane compounds.
Industrial applicability
The 1-aza-5-gerza-5-bromobicyclo [3.3.3] undecane and 1-aza-5-gerza-5-hydrobicyclo [3.3.3] undecane compounds of the invention can be used for synthesizing 1-aza-5-gerza-5-alkylbicyclo [3.3.3] undecane compounds with abundant structures, the properties of the compounds are stable in air, the compounds can exist stably, the raw materials are easy to obtain, the compounds are important raw materials for synthesizing alkylgermanium metal reagents, and the compounds are expected to have important application prospects in industry.
Claims (7)
1. A process for preparing a 1-aza-5-germyl-5-Rbicyclo [3.3.3] undecane compound, wherein R is bromo or hydrogen, and the 1-aza-5-germyl-5-Rbicyclo [3.3.3] undecane compound has the structure shown below,
the method comprises the following steps:
c) preparation of 1-aza-5-gera-5-alkylbicyclo [3.3.3] undecane: reacting 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane with an alkyl Grignard reagent in a solvent at room temperature for 4-6 hours under an inert atmosphere, and quenching the reaction to obtain 1-aza-5-germyl-5-alkylbicyclo [3.3.3] undecane;
d) preparation of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane: dropwise adding liquid bromine into the 1-aza-5-germyl-5-alkyl bicyclo [3.3.3] undecane obtained in the step c) in a solvent to obtain a white solid product; and
e) alternatively, 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane is prepared: under inert atmosphere, adding lithium aluminum hydride into the 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane obtained in the step d) in a solvent, and reacting at room temperature for 1-2 hours to obtain the product 1-aza-5-germyl-5-hydrobicyclo [3.3.3] undecane.
2. The process of claim 1, wherein the 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane is prepared by a process comprising:
a) preparation of zirconocene hydrochloride: under inert atmosphere, stirring zirconocene dichloride and lithium aluminum hydride in a solvent at room temperature for 3-4 hours, and separating to obtain white solid zirconocene hydrochloride; and
b) preparation of 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane: stirring triallylamine compound and the zirconocene hydrochloride obtained in the step b) in a solvent for 1-2 hours at room temperature under inert atmosphere until the solution is clear, then slowly dropwise adding germanium tetrachloride under inert atmosphere, and then placing the reaction solution at 60-80 ℃ for reaction for 8-12 hours to obtain the 1-aza-5-gerdoped-5-chlorobicyclo [3.3.3] undecane.
3. The method of claim 2, wherein in step a), the molar ratio of zirconocene dichloride to lithium aluminum hydride is 3.0-4.5: 1.
4. The process according to claim 2, wherein in step b) the molar ratio of zirconocene hydrochloride to triallylamine compound is from 3.1 to 3.7: 1.
5. The process according to claim 2, wherein in step b) the molar ratio of germanium tetrachloride to triallylamine compound is 1.1-2.5: 1.
6. The process of claim 1, wherein in step c) the molar ratio of alkyl grignard reagent to 1-aza-5-germyl-5-chlorobicyclo [3.3.3] undecane is 2.0-5.0: 1.
7. The process of claim 2, wherein in step e) the molar ratio of 1-aza-5-germyl-5-bromobicyclo [3.3.3] undecane to reducing agent is 0.5-1.5: 1.
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Non-Patent Citations (4)
| Title |
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| Internal Coordination at Tin Promotes Selective Alkyl Transfer in the Stille Coupling Reaction;Edwin Vedejs et al.,;《J.Am.Chem.Soc.》;19921231;第114卷;第6556-6558页，参见第6556页右栏第1段 * |
| Palladium-catalyzed reaction of 1-aza-5-germa-5-organobicyclo[3.3.3]undecane with aryl bromide;Masanori Kosugi et al.,;《Journal of Organometallic Chemistry》;19960719;第508卷;第255-257页，参见第256页左栏最后1段 * |
| Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides;Ling Li et al.,;《Nature Chemistry》;20130519;第5卷;第607-612页 * |
| Theoretical study of the geometrical, energetic and NMR properties of atranes;Marta Marín-Luna et al.,;《Journal of Organometallic Chemistry》;20150710;第794卷;第206-215页，参见第208页表1 * |
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