阅读说明：本技术 一种手性含氮杂芳环化合物的催化不对称合成方法 (Catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compound ) 是由 毛斌 孟鑫 陈祉威 王建飞 张朝焕 俞传明 于 2020-07-07 设计创作，主要内容包括：本发明公开了一种手性含氮杂芳环化合物的催化不对称合成方法,它以手性联萘酚衍生物为催化剂,在有机溶剂及添加剂存在下,式III所示的有机烯基硼试剂对式I或II所示的β-烯基取代的含氮杂芳基类化合物进行不对称1,4-加成反应,生成如式IV或V所示的含有一个手性中心的β-烯基取代的含氮杂环芳环化合物,反应式如下：<Image he="340" wi="700" file="DDA0002572862100000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明利用一种新型多氟联萘酚骨架的催化剂,并采用烯基氟硼酸钾盐作为亲核试剂,在添加剂的作用下,高效制备了多种β-烯基取代的含氮手性杂芳环化合物。本发明底物适用范围广,反应条件简单温和,所得高光学活性的产物可进一步转化为多种医药中间体或者农业工业品,具有较高的科学研究及实际应用价值。(The invention discloses a catalytic asymmetric synthesis method of a chiral nitrogen-containing heteroaromatic ring compound, which takes a chiral binaphthol derivative as a catalyst, and carries out asymmetric 1, 4-addition reaction on β -alkenyl substituted nitrogen-containing heteroaromatic group compounds shown in formula I or II by using an organic alkenyl boron reagent shown in formula III in the presence of an organic solvent and an additive to generate β -alkenyl substituted nitrogen-containing heterocyclic aromatic ring compounds containing a chiral center shown in formula IV or V, wherein the reaction formula is as follows: the invention utilizes a novel catalyst with a polyfluorinated binaphthol skeleton, adopts alkenyl potassium fluoborate as a nucleophilic reagent, and efficiently prepares various β -alkenyl substituted nitrogen-containing chiral heteroaromatic ring compounds under the action of an additive.)

1. A catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic compounds is characterized in that chiral binaphthol derivatives are used as catalysts, in the presence of organic solvents and additives, an organic alkenyl boron reagent shown in a formula III performs asymmetric 1, 4-addition reaction on beta-alkenyl substituted nitrogen-containing heteroaromatic compounds shown in a formula I or II to generate beta-alkenyl substituted nitrogen-containing heterocyclic aromatic ring compounds containing a chiral center shown in a formula IV or V, and the reaction formula is as follows:

x is selected from one of the following: o, S or N; when X is selected from N, the X is also connected with a protecting group, and the protecting group is a Cbz, Boc, Tos, Fmoc, Phth, Suc, PMB, DMB, PMP, Bn, TFA, Trt or Ns group;

[B]is BF₃K、B(OH)₂Or B (pin), preferably BF₃K；

In the formula I and the formula IV, H on a benzene ring is substituted by a substituent R¹Mono-or polysubstituted, n is an integer of 1 to 4 and represents a substituent R on the benzene ring¹The number of the substituent R on the benzene ring at different substituted positions¹The same or different;

in the formulae II and V, H on the nitrogen-containing heterocycle is substituted by a substituent R¹Mono-or di-substituted, n is an integer of 1 to 2 and represents a substituent R on the nitrogen-containing heterocyclic ring¹The number of the substituent groups R on different substitution positions on the nitrogen-containing heterocycle is the same or different;

in the formulas I, II, IV and V, R is¹The substituent is H, halogen, C₁～C₁₀Alkyl radical, C₁～C₅Alkoxy or C₆～C₃₀An aryl group; wherein R is¹The halogen is preferably fluorine, chlorine or bromine; said C₁～C₁₀The alkyl group is preferably C₁～C₆An alkyl group; said C₁～C₅Alkoxy is preferably methoxy or ethoxy; said C₆～C₃₀Aryl is preferably C₆～C₁₈Aryl of (a);

R²selected from one of the following: c₁～C₁₀Alkyl radical, C₁～C₁₂Ester group, C₈～C₁₂Aryl alkynes, C₆～C₃₀Aryl, C having 1-3 heteroatoms selected from N, S and O₃～C₁₂A heteroaryl group; wherein R is²In (b), the C₁～C₁₀The alkyl group is preferably C₁～C₈An alkyl group; said C₁～C₁₂The ester group is preferably C₁～C₄An ester group; said C₈～C₁₂The arylalkyne is preferably C₈～C₁₀An aryl alkyne; said C₆～C₃₀Aryl is preferably C₆～C₂₄Aryl of (a); c having 1 to 3 heteroatoms selected from N, S and O₃～C₁₂Heteroaryl is preferably C containing 1 heteroatom selected from N, S and O₃～C₁₀A heteroaryl group;

R³selected from one of the following: c₃～C₁₀Alkyl radical, C₃～C₁₀Haloalkyl, C₃～C₈Cycloalkyl or cycloalkenyl radical, C₆～C₂₀Aryl, C having 1-3 heteroatoms selected from N, S and O₃～C₁₀A heteroaryl group; wherein R is³In (b), the C₃～C₁₀The alkyl group is preferably C₃～C₆An alkyl group; c₃～C₁₀Haloalkyl is preferably C₃～C₆A haloalkyl group; said C₃～C₈The cycloalkyl or cycloalkenyl radical is preferably C₃～C₆Cycloalkyl or cycloalkenyl radicals; said C₆～C₂₀Aryl is preferably C₆～C₁₈An aryl group; c having 1 to 3 heteroatoms selected from N, S and O₃～C₁₀Heteroaryl is preferably C containing one or two oxygen or sulfur heteroatoms₃～C₈A heteroaryl group.

2. The catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compound of claim 1, wherein R is¹In which halogen is a chlorine atom, C₁～C₆Alkyl is methyl, C₆～C₁₈Aryl of (a) is phenyl; in the formula²In, C₁～C₈Alkyl is methyl, n-propyl or isopropyl, etc., C₁～C₄The ester group is an ethyl ester group, C₈～C₁₀Aryl alkynes are phenylacetylene, C₆～C₂₄Aryl of (a) is phenyl, methylphenyl, bromophenyl, methoxyphenyl or nitrophenyl, C containing 1 heteroatom selected from N, S and O₃～C₁₀Heteroaryl is furyl, thienyl or bromopyridyl; the R is³In, C₃～C₆Alkyl is butyl, C₃～C₆Haloalkyl being 4-chlorobutyl, C₃～C₆The cycloalkyl or cycloalkenyl is cyclobutyl or cycloHexyl or cyclohexenyl radical, C₆～C₁₈Aryl is phenyl, fluorophenyl, methylphenyl, trifluoromethylphenyl, chlorophenyl, nitrophenyl or naphthyl, said C containing one or two oxygen or sulfur heteroatoms₃～C₈Heteroaryl is thienyl.

3. The catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compounds as claimed in claim 1, characterized in that the β -alkenyl substituted nitrogen-containing heteroaromatic group compounds shown in formula I or II are selected from one of the following:

4. the catalytic asymmetric synthesis process of a chiral nitrogen-containing heteroaromatic ring compound of claim 1, wherein the organoalkenylboron reagent of formula III is selected from one of the following:

5. the method for the catalytic asymmetric synthesis of a chiral nitrogen-containing heteroaromatic ring compound as claimed in claim 1, wherein the chiral binaphthol derivative is selected from one of the following:

6. the catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compound according to claim 1, characterized in that the reaction temperature is 50 ℃ to 70 ℃, preferably 60 ℃; the organic solvent is toluene, trifluorotoluene, fluorobenzene, dichloromethane, tetrahydrofuran or 1, 2-dichloroethane, preferably toluene or trifluorotoluene.

7. The catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compounds as claimed in claim 1, characterized in that the mass ratio of the organic alkenyl boron reagent shown in formula III to the beta-alkenyl substituted nitrogen-containing heteroaromatic group compound shown in formula I or II is 1.5-4: 1, preferably 2-3: 1; the mass ratio of the catalyst to the beta-alkenyl substituted nitrogen-containing heteroaryl compound shown in the formula I or II is 0.5-50: 100, preferably 20: 100; the ratio of the amount of the beta-alkenyl substituted nitrogen-containing heteroaryl compound shown in the formula I or II to the volume of the organic solvent is 0.05-0.5: 1, the amount of the substance is mmol, and the volume is mL.

8. The method for the catalytic asymmetric synthesis of a chiral nitrogen-containing heteroaromatic ring compound of claim 1, wherein the additive is at least one of molecular sieve, lithium bromide, lithium chloride, lithium iodide and boron trifluoride diethyl etherate, and is preferably a mixed additive of molecular sieve or a combination of molecular sieve and lithium bromide.

9. The catalytic asymmetric synthesis method of chiral nitrogen-containing heteroaromatic ring compound of claim 8, wherein the additive is molecular sieve of the type

10. The method of claim 8, wherein the additive is selected from the group consisting of

Technical Field

The invention relates to a catalytic asymmetric synthesis method of a chiral nitrogen-containing heteroaromatic ring compound

Background

Chiral nitrogen-containing heteroaromatic ring compounds are core units of many natural products, agricultural industrial products, bioactive compounds and drug molecules, and have important application in the field of biomedicine. In addition, professor Njardarson made an overview of nitrogenous drugs in 2014. It is mentioned herein that the FDA approved drug database in the united states shows that 59% of unique small molecule drugs contain at least one nitrogen heterocycle [ Vitaku, e.; smith, d.t.; njardarson, J.T. journal of medicinal chemistry.2014,57,10257-10274 ]. In view of the common application of nitrogen-containing heteroaromatic compounds (such as imidazole, oxazole, thiazole and pyridine) in medicines, the structures are generally obtained by conjugate addition of a nucleophilic reagent to a beta-alkenyl nitrogen-containing compound, and the functional groups are converted to obtain wider application. In 1998 Reider used a new nickel catalyst to catalyze the addition of aryl, vinyl or alkyl grignard reagents to 4-substituted vinylpyridines, but the product had an ee value of only 15% [ Houpis, i.n.; lee, j.; dorziotis, d.; molina, a.; reamer, B.; volante, r.p.; reider, P.J.tetrahedron.1998,54,1185-1195 ]. In 2010, under the concerted catalysis of a novel chiral diene ligand and rhodium metal, a Lam subject group adopts aryl boric acid or aryl boric acid ester to carry out a conjugate asymmetric addition reaction on an alkenyl heteroaromatic compound, so that higher enantioselectivity is obtained, but the reaction system is not suitable for an alkenyl boric acid nucleophile [ Graham, P.; lam, H.W.J.am.chem.Soc.2010,132,14373-14375 ]. In 2016, Harutyunyan developed a chiral copper catalyst with chelating diphosphine ligands, and realized that a grignard reagent performs asymmetric addition reaction on a lewis acid-activated conjugated nitrogen-containing heteroaromatic substrate [ Jumde, r.t.; lanza, f.; veenstra m.j.; harutyunyan, S.R. Science2016,352,433-437 ].

Chiral 1, 1' -Binaphthol (BINOL) derivatives are of great interest for their superior chiral control properties and are used in a variety of asymmetric catalytic reactions. In 2005, Chong topic group adopted 3, 3' -iodo chiral binaphthol as a catalyst, and alkynyl borate as a nucleophile to perform asymmetric conjugate addition reaction on an ketene compound, so as to obtain an addition product [ Wu, t.r.; chong, J.M; J.am.chem.Soc.2005,127,3244-3245 ]. In 2007, the subject group adopts the same catalyst to realize the asymmetric conjugate addition reaction of alkenyl borate on the ketene compound, and an addition product [ Wu, T.R.; chong, J.M; J.am.chem.Soc.2007,129,4908-4909 ].

In summary, many reports of the conjugated asymmetric addition reaction of the chiral metal catalyst to the alkenyl nitrogen-heteroaromatic ring compound are found in literature research, but how to efficiently realize the asymmetric addition reaction of the organic boron reagent to the alkenyl nitrogen-heteroaromatic ring compound catalyzed by the organic small molecule is not solved. There are also difficulties associated with the addition of olefins substituted nitrogen containing heterocyclic aryl compounds in the beta position: 1) the substrate has low activity, and the steric hindrance is increased by the substitution of the beta position, so that the reaction activity is further reduced. 2) The metal reagent can coordinate with the heteroaryl substrate or other reagent during the reaction to interfere with the proper progress of the reaction. 3) The conformation of the acyclic system is relatively flexible, and the enantioselectivity of the product is difficult to control. Meanwhile, the existing method for the addition reaction of the heterocyclic aryl compound substituted by the beta-alkenyl has some defects: a) the existing literature is mainly based on metal catalysis for C-C bond construction, relatively harsh reaction conditions and poor functional group compatibility. b) The applicable substrate range of the catalytic system is narrow, and the diversity of the nucleophilic reagent needs to be enhanced. c) Derivatization and practicability of the product need to be improved. Aiming at the difficulties and the defects, the invention aims to solve the technical problem of realizing the high-efficiency catalytic asymmetric synthesis of the chiral nitrogen-containing heteroaromatic ring compound by developing a method with wide substrate and nucleophile range, simplicity, easy obtaining and good functional group compatibility.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and develop a catalytic asymmetric synthesis method of a chiral nitrogen-containing heteroaromatic ring compound, which uses 6, 6' -substituted pentafluoroethyl modified chiral binaphthol as a catalyst and uses simple and easily-obtained alkenyl fluorine potassium borate with good stability as a nucleophilic reagent to realize the high-efficiency asymmetric addition reaction of the chiral binaphthol on a beta alkenyl substituted nitrogen-containing heteroaromatic ring compound.

The catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that a chiral binaphthol derivative is used as a catalyst, in the presence of an organic solvent and an additive, an organic alkenyl boron reagent shown in a formula III performs asymmetric 1, 4-addition reaction on a beta-alkenyl substituted nitrogen-containing heteroaromatic group compound shown in a formula I or II to generate a beta-alkenyl substituted nitrogen-containing heteroaromatic ring compound containing a chiral center shown in a formula IV or V, and the reaction formula is as follows:

x is selected from one of the following: o, S or N; when X is selected from N, the X is also connected with a protecting group, and the protecting group is Cbz, Boc, Tos, Fmoc, Phth, Suc, PMB, DMB, PMP, Bn, TFA, Trt or Ns.

[B]Is BF₃K、B(OH)₂Or B (pin), preferably BF₃K。

In the formula I and the formula IV, H on a benzene ring is substituted by a substituent R¹Mono-or polysubstituted, n is an integer of 1 to 4 and represents a substituent R on the benzene ring¹The number of the substituent R on the benzene ring at different substituted positions¹The same or different.

In the formulae II and V, H on the nitrogen-containing heterocycle is substituted by a substituent R¹Mono-or di-substituted, n is an integer of 1 to 2 and represents a substituent R on the nitrogen-containing heterocyclic ring¹The number of the substituent groups R on different substituted positions on the nitrogen-containing heterocycle is the same or different.

In the formulas I, II, IV and V, R is¹The substituent is H, halogen, C₁～C₁₀Alkyl radical, C₁～C₅Alkoxy or C₆～C₃₀An aryl group; wherein R is¹The halogen is preferably fluorine, chlorine or bromine; said C₁～C₁₀The alkyl group is preferably C₁～C₆An alkyl group; said C₁～C₅Alkoxy is preferably methoxy or ethoxy; said C₆～C₃₀Aryl is preferably C₆～C₁₈Aryl group of (1).

R²Selected from one of the following: c₁～C₁₀Alkyl radical, C₁～C₁₂Ester group, C₈～C₁₂Aryl alkynes, C₆～C₃₀Aryl, C having 1-3 heteroatoms selected from N, S and O₃～C₁₂A heteroaryl group; wherein R is²In (b), the C₁～C₁₀The alkyl group is preferably C₁～C₈An alkyl group; said C₁～C₁₂The ester group is preferably C₁～C₄An ester group; said C₈～C₁₂The arylalkyne is preferably C₈～C₁₀An aryl alkyne; said C₆～C₃₀Aryl is preferably C₆～C₂₄Aryl of (a); c having 1 to 3 heteroatoms selected from N, S and O₃～C₁₂Heteroaryl is preferably C containing 1 heteroatom selected from N, S and O₃～C₁₀A heteroaryl group.

R³Selected from one of the following: c₃～C₁₀Alkyl radical, C₃～C₁₀Haloalkyl, C₃～C₈Cycloalkyl or cycloalkenyl radical, C₆～C₂₀Aryl, C having 1-3 heteroatoms selected from N, S and O₃～C₁₀A heteroaryl group; wherein R is³In (b), the C₃～C₁₀The alkyl group is preferably C₃～C₆An alkyl group; c₃～C₁₀Haloalkyl is preferably C₃～C₆A haloalkyl group; said C₃～C₈The cycloalkyl or cycloalkenyl radical is preferably C₃～C₆Cycloalkyl or cycloalkenyl radicals; said C₆～C₂₀Aryl is preferably C₆～C₁₈An aryl group; c having 1 to 3 heteroatoms selected from N, S and O₃～C₁₀Heteroaryl is preferably C containing one or two oxygen or sulfur heteroatoms₃～C₈A heteroaryl group.

Further, said R¹In which halogen is a chlorine atom, C₁～C₆Alkyl is methyl, C₆～C₁₈Aryl of (a) is phenyl; in the formula²In, C₁～C₈Alkyl is methyl, n-propyl or isopropyl, etc., C₁～C₄The ester group is an ethyl ester group, C₈～C₁₀Aryl alkynes are phenylacetylene, C₆～C₂₄Aryl of (a) is phenyl, methylphenyl, bromophenyl, methoxyphenyl or nitrophenyl, C containing 1 heteroatom selected from N, S and O₃～C₁₀Heteroaryl is furyl, thienyl or bromopyridyl; the R is³In, C₃～C₆Alkyl is butyl, C₃～C₆Haloalkyl being 4-chlorobutyl, C₃～C₆The cycloalkyl or cycloalkenyl is cyclobutyl, cyclohexyl or cyclohexenyl, C₆～C₁₈Aryl is phenyl, fluorophenyl, methylphenyl, trifluoromethylphenyl, chlorophenyl, nitrophenyl or naphthylC containing one or two oxygen or sulfur heteroatoms₃～C₈Heteroaryl is thienyl.

The beta-alkenyl substituted nitrogen-containing heteroaryl compound shown in the formula I or II is selected from one of the following compounds:

the catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the organic alkenyl boron reagent shown in the formula III is selected from one of the following reagents:

the catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the chiral binaphthol derivative is selected from one of the following compounds:

the catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the reaction temperature is 50-70 ℃, and preferably 60 ℃; the organic solvent is toluene, trifluorotoluene, fluorobenzene, dichloromethane, tetrahydrofuran or 1, 2-dichloroethane, preferably toluene or trifluorotoluene.

The catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the mass ratio of the organic alkenyl boron reagent shown in the formula III to the beta-alkenyl substituted nitrogen-containing heteroaromatic group compound shown in the formula I or II is 1.5-4: 1, preferably 2-3: 1; the mass ratio of the catalyst to the beta-alkenyl substituted nitrogen-containing heteroaryl compound shown in the formula I or II is 0.5-50: 100, preferably 20: 100; the ratio of the amount of the beta-alkenyl substituted nitrogen-containing heteroaryl compound shown in the formula I or II to the volume of the organic solvent is 0.05-0.5: 1, the amount of the substance is mmol, and the volume is mL.

The catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic compound is characterized in that the additive is at least one of molecular sieve, lithium bromide, lithium chloride, lithium iodide and boron trifluoride diethyl etherate, and is preferably a mixed additive of the molecular sieve or the combination of the molecular sieve and the lithium bromide.

The catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the additive is a molecular sieve with the type number of the molecular sieveMolecular sieve,Molecular sieves orThe mass ratio of the molecular sieve to the amount of the β -alkenyl substituted heteroaryl compound shown in the formula II or III is 1-2.5: 1, the unit of the mass is g, and the unit of the amount of the substance is mmol.

The catalytic asymmetric synthesis method of the chiral nitrogen-containing heteroaromatic ring compound is characterized in that the additive isA mixed additive of a molecular sieve in combination with lithium bromide,the mass ratio of the molecular sieve to the lithium bromide is 4-6: 1, the mass ratio of the additive to the substance amount of the β -alkenyl substituted heteroaryl compound shown in the formula II or III is 1-2.5: 1, the unit of the mass is g, and the unit of the substance amount is mmol.

Compared with the prior art, the invention has the following advantages:

1. for 1, 4-asymmetric conjugate addition of organic alkenyl boron reagent, the prior literature reports are limited to substrates with conjugated carbon-oxygen double bonds and carbon-carbon double bonds, and substrates with conjugated carbon-carbon double bonds and carbon-carbon double bonds are not reported because of weak activation force of carbon-oxygen part. The invention develops a novel activation mode through the synergistic action of the newly developed chiral binaphthol catalyst and various additives, successfully creates a precedent of the asymmetric conjugate addition reaction of the organic alkenyl boron reagent to the beta-alkenyl substituted heteroaryl compound, and has extremely high scientific research value and creativity.

2. For substrates such as beta-alkenyl substituted nitrogen heteroaromatic rings, the construction of double bond sites is limited to nitrogen heterocyclic or thiol nucleophiles. The invention firstly uses the easily obtained organic alkenyl boron reagent taking carbon as the center as the nucleophilic reagent, creates an active skeleton with various medicinal values, and has extremely high practicability and development prospect.

3. Currently, the carbon-carbon bond formation for substrates such as β -alkenyl substituted nitrogen heteroaromatic rings is limited to transition metal catalyzed arylation or alkylation reactions. The invention efficiently constructs a large amount of alpha-alkenyl substituted products with high optical activity in a mild reaction environment by simple organic catalysis, and has extremely high economical efficiency and environmental protection.

4. Compared with the Chinese patent CN 202010026393.9 disclosed by the applicant, the invention changes 6, 6' -substituted groups in the existing catalyst system in a laboratory, introduces pentafluoroethyl with strong electron-withdrawing capability, improves the Lewis acid acidity of the alkenyl boron-chiral binaphthol intermediate by structural modification of the catalyst, and is beneficial to controlling the conversion rate and enantioselectivity of the product. Meanwhile, the catalyst is the first research on the application of the catalyst to the reaction.

5. The invention has wide applicable substrates, and covers various beta-alkenyl substituted heterocyclic aryl compounds (including imidazole, thiazole, oxazole and partial pyridine substrates). The wide range is also the first research of the similar documents, and simultaneously, the substrates and the products after addition are key mother ring structures of various medicaments.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

Analytical apparatus Using B ü chiB-54Melting point was measured by 0 capillary melting point apparatus. Comprises that¹H NMR，¹³NMR data including C NMR spectra were recorded on a Bruker400 MHz or 600MHz instrument. All of¹³The C NMR spectra are all broadband proton decoupled.¹Chemical shifts are reported in ppm by H NMR relative to the residual signal of the solvent.¹⁹F NMR used perfluorobenzene as an internal standard. High Resolution Mass (HRMS) was recorded on an Agilent 6210 TOF LC/MS using ESI as the ion source. Optical rotation was measured using an AUTOPOLV automatic polarimeter. The enantiomeric excess value (ee) was determined by HPLC analysis using Agilent 1100 equipped with a Daicel Chiralpak IA, IC, IE, IF, IG column.