Intermolecular hydrogen migration causes cyclammonium β-C (sp3)-H function the method that is combined to the substituted pyrrolidines of β-
阅读说明：本技术 分子间氢迁移引发环胺β-C(sp3)–H官能化合成β-取代的吡咯烷类化合物的方法 (Intermolecular hydrogen migration causes cyclammonium β-C (sp3)-H function the method that is combined to the substituted pyrrolidines of β- ) 是由 肖建 周兰 于 2019-09-04 设计创作，主要内容包括：本发明公开了一种由分子间氢迁移引发环胺β-C(sp~3)–H官能化合成β-取代的吡咯烷类化合物的方法,属于化学合成技术领域。本发明的方法通过分子间氢迁移实现杂原子β-C(sp~3)–H官能化。本方法反应条件温和且底物普适性好；避免传统方法实现胺类化合物β-C(sp~3)–H官能化必须预先安装导向基或者采用过渡金属和外加氧化剂、还原剂等苛刻条件,合成过程绿色、高效、高原子经济性,为氢迁移领域开辟了新的道路。(The invention discloses one kind to cause cyclammonium β-C (sp by intermolecular hydrogen migration 3 ) method that-H function is combined to the substituted pyrrolidines of β-, belong to chemosynthesis technical field.Method of the invention realizes hetero atom β-C (sp by intermolecular hydrogen migration 3 )-H functionalization.This method reaction condition is mild and substrate universality is good；Conventional method is avoided to realize aminated compounds β-C (sp 3 )-H functionalization must install guiding base in advance or using the harsh conditions such as transition metal and oxidant applying, reducing agent, synthesis process green, efficient, high atom economy open new road for hydrogen migration field.)
1. a kind of cause cyclammonium β-C (sp by intermolecular hydrogen migration3)-H function is combined to the sides of the substituted pyrrolidines of β- Method, which is characterized in that be by aromatic amine compounds I and ketone acid esters compound ii as reaction substrate, through intermolecular hydrogen migration Cause cyclammonium β-C (sp3)-H is functionalized, chemical equation is as follows:
Wherein,
Dotted line indicates whether or not there is；
R is C1-C3Alkyl, halogen, methoxyl group, ester group, boric acid, acetyl group, phenyl, 4-F-C6H4-、4-Me-C6H4Or without in Any one；
R1It is trifluoromethyl or-CO2Any one in Et；
R2It is C1-C3Any one in alkyl.
2. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 13)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the catalyst is trifluoromethayl sulfonic acid, camphorsulfonic acid, p-methyl benzenesulfonic acid, dinaphthalene One in phenol phosphate, trifluoroacetic acid, trifluoromethanesulfonic acid scandium, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc or trifluoromethanesulfonic acid indium Kind.
3. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 23)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the catalyst is trifluoromethayl sulfonic acid.
4. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 13)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the reaction temperature is 60 DEG C.
5. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 13)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the solvent is 1,2- dichloroethanes, n-hexane, chloroform, toluene, dioxanes, four Hydrogen furans or dimethyl sulfoxide.
6. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 53)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the solvent is 1,2- dichloroethanes.
7. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 13)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the amount ratio of the aromatic amine compounds and ketone acid ester type compound be 1:1.5~ 2:1。
8. causing cyclammonium β-C (sp by intermolecular hydrogen migration according to claim 13)-H function is combined to the substituted pyrroles of β- The method of alkyl compound, which is characterized in that the compound III is with any one in flowering structure:
9. causing cyclammonium β-C (sp by intermolecular hydrogen migration described in any one according to claim 1~83)-H function is combined to β-and takes The method of the pyrrolidines in generation, which is characterized in that steps are as follows:
Reaction substrate aromatic amine compounds and ketone acid esters compound mole ratio 1.2:1 add the reaction of 10mol% in a solvent Catalyst reacts under the conditions of 60 DEG C；It is monitored and is reacted by thin-layer chromatography, after the reaction was completed, concentrated by rotary evaporation, column chromatography for separation are pure Change, obtains product.
10. the β-of claim 9 the method synthesis substituted pyrrolidines.
Technical field
The present invention relates to chemosynthesis technical fields, in particular to a kind of to cause cyclammonium β-C by intermolecular hydrogen migration (sp3)-H function the method that is combined to the substituted pyrrolidines of β-.
Background technique
Heterocyclic compound containing cyclammonium skeleton is widely present in drug and natural products, it is also that secondary amine chirality is urged The important composition of agent and containing n-donor ligand.The derivative of cyclic amine compound is significant in organic synthesis and drug development, letter The high method of single operability can save many times for synthetic work person, provide new chemical combination for the discovery of drug molecule Object database.C (sp directly is carried out to cyclammonium3)-H functionalization is deriving mode the most efficient, but most work at present All put into its α-C (sp3)-H functionalization, about cyclammonium β-C (sp3)-H report it is still less.This is without substituted suspected of β- The development and application of cyclammonium analog derivative bring predicament.Traditional method, Yao Shixian aminated compounds β-C (sp3)-H function Change, it is necessary to which installation in advance is oriented to base or uses the harsh conditions such as transition metal and oxidant applying, reducing agent, as follows:
These methods not only need additional synthesis step, the oxidant of expensive transition metal or Additional equivalents or also Former agent does not meet the synthesis theory being the theme now with green, efficient, high atom economy.Therefore exploitation is simply without metal The synthetic method of catalysis is significant in this field.
(2019,55 (9): Chemical Communication 1217-1220) passes through B (C for Ma seminar6F5)3Catalysis Neutral alumina reduction strategy realize β-alkylation of tertiary amine.
The reaction passes through B (C6F5)3B (C is formed after seizing hydrogen to tertiary amine β-position6F5)3- H species and imines ion, by interconversion The substituted imines ion of conjugate addition generation β-is carried out with to methylene quinone after isomery, finally B (the C by originally being formed6F5)3-H The target product that species restore to the end.The reaction realizes the β-C (sp of the amine of neutral alumina reduction for the first time3)-H function Change, but still has some deficits in terms of amine substrate universality.
Summary of the invention
Aiming at the problems existing in the prior art, the purpose of the present invention is to provide one kind causes ring by intermolecular hydrogen migration Amine β-C (sp3)-H function the method that is combined to the substituted pyrrolidines of β-.
One kind causing cyclammonium β-C (sp by intermolecular hydrogen migration3)-H function is combined to the substituted pyrrolidines of β- Method, be by aromatic amine compounds I and ketone acid esters compound ii as reaction substrate, through intermolecular hydrogen migration initiation ring Amine β-C (sp3)-H is functionalized, chemical equation is as follows:
Wherein,
Dotted line indicates whether or not there is；
R is C1-C3Alkyl, halogen, methoxyl group, ester group, boric acid, acetyl group, phenyl, 4-F-C6H4-、4-Me-C6H4Or Without in any one；
R1It is trifluoromethyl or-CO2Any one in Et；
R2It is C1-C3Any one in alkyl.
On the basis of above scheme, the catalyst is trifluoromethayl sulfonic acid, camphorsulfonic acid, p-methyl benzenesulfonic acid, dinaphthalene Phenol phosphate, trifluoroacetic acid, trifluoromethanesulfonic acid scandium, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid zinc or trifluoromethanesulfonic acid indium；
Preferably, trifluoromethayl sulfonic acid is selected to make catalyst.
On the basis of above scheme, the dosage of the trifluoromethayl sulfonic acid is 10mol%.
On the basis of above scheme, the reaction temperature is 60 DEG C.
On the basis of above scheme, the solvent is 1,2- dichloroethanes, n-hexane, chloroform, toluene, dioxanes, four Hydrogen furans or dimethyl sulfoxide.
Preferably, 1,2- dichloroethanes is selected to make solvent.
On the basis of above scheme, the amount ratio of the aromatic amine compounds and ketone acid ester type compound be 1:1.5~ 2:1。
On the basis of above scheme, the compound III is specifically included with flowering structure:
It is described that cyclammonium β-C (sp is caused by intermolecular hydrogen migration on the basis of above scheme3)-H function is combined to β-and takes The method of the pyrrolidines in generation, the specific steps are as follows:
Reaction substrate aromatic amine compounds and ketone acid esters compound mole ratio 1.2:1 add 10mol%'s in a solvent Catalysts react under the conditions of 60 DEG C；It is monitored and is reacted by thin-layer chromatography, after the reaction was completed, concentrated by rotary evaporation, column chromatography It isolates and purifies, obtains product.
The β-of above method synthesis substituted pyrrolidines.
Reaction mechanism is: InAcid activation under, a small amount of trifluoroacetone acetoacetic ester as intermolecular hydrogen by Body receives the negative hydrogen of N- aryl-pyrrolidine alkane nitrogen-atoms alpha-position, generates iminium cations intermediate I and causes the reaction.Then intermediate Body I is converted into intermediate II by the interconversion of alkene imines, be changed into the intermediate II of enamine to byThe three of acid activation Nucleophilic attack (carbonyl-ene reaction) occurs for fluoropyruvate ethyl ester, by another molecule N- aryl-pyrrolidine alkane after generation intermediate III The negative hydrogen reduction of nitrogen-atoms alpha-position generates target product 3.At the same time, another molecule N- aryl-pyrrolidine alkane 1 is converted into Asia again Amine cation intermediate I continues next catalytic cycle.Entire reaction mechanism is divided into two parts, and first part causes A small amount of trifluoroacetone acetoacetic ester is only needed to participate in, subsequent neutral alumina reduction process is in occupation of leading position.
The invention has the advantages that: reaction condition, mild and substrate universality is good；Green, efficient, the high atom warp of synthesis process Ji property；Hydrogen transfer reaction is solved in C (sp3)-H functionalization neighborhood can only realize hetero atom α-C (sp3)-H functionalization and can not Realize hetero atom β-C (sp3)-H is functionalized this problem in science.By careful mechanism study, a kind of hydrogen intermolecular twice is moved The process of shifting is confirmed that this is also that hydrogen migration field opens new road.
Detailed description of the invention
Fig. 1 is compound 3a in the embodiment of the present invention 21H H NMR spectroscopy
Fig. 2 is compound 3a in the embodiment of the present invention 213C H NMR spectroscopy
Fig. 3 is compound 3a in the embodiment of the present invention 219F H NMR spectroscopy
Specific embodiment
Term as used in the present invention generally has those of ordinary skill in the art usual unless otherwise specified The meaning of understanding.
Combined with specific embodiments below, and referring to the data further detailed description present invention.Following embodiment only be It illustrates the present invention, rather than limits the scope of the invention in any way.
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