阅读说明：本技术 一种β-氨基腈类化合物及其制备方法 (Beta-amino nitrile compound and preparation method thereof ) 是由 张鸽 熊涛 张前 于 2020-06-24 设计创作，主要内容包括：本发明提供一种β-氨基腈类化合物及其制备方法,属于有机合成化学技术领域。该化合物的结构通式如式Ⅰ或式Ⅱ所示。本发明还提供一种β-氨基腈类化合物的制备方法,该方法包括：在反应容器中加入催化剂、手性膦配体和溶剂,室温下搅拌,然后加入肉桂腈衍生物和羟胺衍生物继续搅拌,最后再加入氢硅烷,室温反应,得到具有高立体选择性的手性β-氨基腈类化合物。本发明的手性β-氨基腈类化合物具有良好的对映选择性,通过高效液相色谱实验证明其ee值最高可达99％。(The invention provides a beta-amino nitrile compound and a preparation method thereof, belonging to the technical field of organic synthetic chemistry. The structural general formula of the compound is shown as a formula I or a formula II. The invention also provides a preparation method of the beta-aminonitrile compound, which comprises the following steps: adding a catalyst, a chiral phosphine ligand and a solvent into a reaction vessel, stirring at room temperature, then adding a cinnamonitrile derivative and a hydroxylamine derivative, continuously stirring, finally adding hydrosilane, and reacting at room temperature to obtain the chiral beta-aminonitrile compound with high stereoselectivity. The chiral beta-amino nitrile compound has good enantioselectivity, and the ee value of the chiral beta-amino nitrile compound can reach 99% at most through high performance liquid chromatography experiments.)

1. a beta-amino nitrile compound, which is characterized in that the structural general formula of the compound is shown as a formula I or a formula II:

in the formula I, R¹is-H, -CH₃、-OCH₃、-SCH₃、-OPh、-Ph、-F、-Cl、-Br；

R²Is selected from benzyl;

R³selected from benzyl,

In the formula II, X is selected from O or S.

2. The β -aminonitrile compound according to claim 1, wherein the β -aminonitrile compound has a structure represented by 2a to 2 p:

3. the method according to claim 1, wherein the method comprises:

under the condition of nitrogen, adding a catalyst, a chiral diphosphine ligand and a solvent into a reaction vessel, stirring at room temperature, then adding a cinnamonitrile derivative and a hydroxylamine derivative, continuously stirring, and then adding hydrosilane to react to obtain the beta-aminonitrile compound.

4. The method according to claim 3, wherein the catalyst is anhydrous cupric acetate.

5. The method according to claim 3, wherein the chiral diphosphine ligand is (S, S) -Ph-BPE.

6. The method according to claim 3, wherein the cinnamonitrile derivative is trans-cinnamonitrile, 2-methylcinnamonitrile, 3-methoxycinnamonitrile, 4-methylthiocinnamonitrile, 4-phenylcinnamonitrile, 4-acetoxycinnamonitrile, 3- (4-fluoro-3-phenoxyphenyl) acrylonitrile, 3-fluorocinnamonitrile, 2-chlorocinnamonitrile, 2-bromocinnamonitrile, 3-trifluoromethoxy-cinnamonitrile, or 3-trifluoromethyl-cinnamonitrile.

7. The method of claim 3, wherein the hydroxylamine derivative is selected from the group consisting of o-benzoyl-n, n-dibenzylhydroxylamine, morpholino benzoate, thioequiline benzoate, o-benzoyl-n-benzyl-n- (4-trifluoromethylbenzyl) hydroxylamine and o-benzoyl-n-benzyl-n- (4-methoxybenzyl) hydroxylamine.

8. The method of claim 3, wherein the hydrosilane is tetramethyldisiloxane, diethoxymethylhydrosilane, or dimethoxymethylhydrosilane.

9. The method according to claim 3, wherein the reaction temperature is room temperature and the reaction time is 12 to 24 hours.

10. The method according to claim 3, wherein the molar ratio of the catalyst to the ligand (S, S) -Ph-BPE to the hydrosilane to the cinnamonitrile derivative to the hydroxylamine derivative is 0.5: 0.5: 3.0: 1.0: 1.2.

Technical Field

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a chiral beta-aminonitrile compound with high enantioselectivity and a carbon stereocenter at a beta position and a preparation method thereof.

Background

Chiral nitrogen-containing compounds are ubiquitous building blocks in natural products, synthetic drugs, and chiral catalysts. The beta-amino nitrile compound with optical activity is a very important synthetic intermediate, and has very wide application in organic synthesis and pharmaceutical chemistry. The chiral beta-amino nitrile compound can be easily converted into optically active beta-amino acid and 1, 3-diamine compound, and can be used for synthesizing optically active ligand, polypeptide and the like. Thus, the asymmetric synthesis of β -amino acids and their derivatives, as well as β -aminonitriles, has been one of the focuses of research and attention in the chemical community. The asymmetric conjugate addition of a catalytic nitrogen nucleophile to alpha, beta-unsaturated nitrile, namely aza-Michael addition reaction, is one of the most direct and effective means for synthesizing chiral beta-aminonitrile and derivatives thereof, and is also a very important reaction in organic synthesis and asymmetric catalysis. However, compared with asymmetric aza-Michael reaction of α, β -unsaturated carbonyl compounds, asymmetric aza-Michael reaction of α, β -unsaturated nitrile compounds is still a challenge, and there is no better method for inducing asymmetry at present, probably due to the lack of rigid environment for the linear structure of-CN itself to act with chiral catalyst. In fact, to our knowledge, only a few examples have been reported, the metal catalysts used are also relatively expensive and, to date, the enantiomeric excess (ee) can only reach 21%. Furthermore, in addition to the above challenges, the monotonic mechanism of control of stereoselectivity by coordination of the chiral catalyst with the-CN functionality may lead to the need to develop new catalytic systems when switching electron withdrawing groups of unsaturated hydrocarbon feedstocks from one-EWG to another-EWG, which is detrimental to the establishment of chiral compound libraries. Therefore, it is very attractive to develop a general-purpose catalytic system with a novel mechanism to realize a method for rapidly preparing chiral beta-aminonitrile compounds from simple and easily available cinnamonitrile raw materials.

With the rapid deterioration of global ecological environment, how to realize sustainable development becomes a major problem facing human beings, and green chemical research, which is centered on eliminating pollution from the source and saving resources, has become a powerful means for solving the increasingly serious ecological environment problem. The asymmetric conjugate addition reaction of the Cu-catalyzed unsaturated nitrile has the advantages of environmental friendliness, low price, practicability, high efficiency and the like, and can effectively construct a chiral center at a beta-position of a-CN functional group. To date, the synthesis of β -aminonitriles with high enantioselectivity via free radical processes has not been reported in the literature.

Disclosure of Invention

The invention aims to provide a beta-amino nitrile compound and a preparation method thereof, wherein the reaction has high stereoselectivity, and the product has high enantioselectivity.

The invention firstly provides a beta-amino nitrile compound, which has a structural general formula shown as a formula I or a formula II:

in the formula I, R¹is-H, -CH₃、-OCH₃、-SCH₃、-OPh、-Ph、-F、-Cl、-Br；

R²Is selected from benzyl;

R³selected from benzyl,

In the formula II, X is selected from O or S.

Preferably, the beta-aminonitrile compound has a structure represented by 2a to 2 p:

the invention also provides a preparation method of the beta-aminonitrile compound, which comprises the following steps:

under the condition of nitrogen, adding a catalyst, a chiral diphosphine ligand and a solvent into a reaction vessel, stirring at room temperature, then adding a cinnamonitrile derivative and a hydroxylamine derivative, continuously stirring, and then adding hydrosilane to react to obtain the beta-aminonitrile compound.

Preferably, the catalyst is anhydrous copper acetate.

Preferably, the chiral diphosphine ligand is (S, S) -Ph-BPE.

Preferably, the cinnamonitrile derivative is trans-cinnamonitrile, 2-methylcinnamonitrile, 3-methoxycinnamonitrile, 4-methylthiocinnamonitrile, 4-phenylcinnamonitrile, 4-acetoxycinnamonitrile, 3- (4-fluoro-3-phenoxyphenyl) acrylonitrile, 3-fluorocinnamonitrile, 2-chlorocinnamonitrile, 2-bromocinnamonitrile, 3-trifluoromethoxy-cinnamonitrile, or 3-trifluoromethyl-cinnamonitrile.

Preferably, the hydroxylamine derivative is oxygen-benzoyl-nitrogen, nitrogen-dibenzylhydroxylamine, morpholinobenzoate, thiomorpholinobenzoate, oxygen-benzoyl-nitrogen-benzyl-nitrogen- (4-trifluoromethylbenzyl) hydroxylamine or oxygen-benzoyl-nitrogen-benzyl-nitrogen- (4-methoxybenzyl) hydroxylamine.

Preferably, the hydrosilane is Tetramethyldisiloxane (TMDS), Diethoxymethylhydrosilane (DEMS) or Dimethoxymethylhydrosilane (DMMS).

Preferably, the reaction temperature is room temperature, and the reaction time is 12 to 24 hours.

Preferably, the molar ratio of the catalyst, ligand (S, S) -Ph-BPE, hydrosilane, cinnamonitrile derivative, and hydroxylamine derivative is 0.5: 0.5: 3.0: 1.0: 1.2.

the invention has the advantages of

The invention firstly provides an β -amino nitrile compound, the structural general formula of which is shown as formula I, and a chiral amino functional group is positioned at β -position of an electron-withdrawing-CN substituent group^IH complex, subsequent reaction of the organocopper intermediate with hydroxylamine derivative to produce LxCu^IIH and alkylamine nitrogen radical with nucleophilicity, addition of nitrogen radical to cinnamonitrile in high regioselectivity to obtain α -carbonyl carbon radical, and final hydrogen atom transferThe β -amino nitrile compound has excellent enantioselectivity, and the ee value of the compound can reach 99% through high performance liquid chromatography experiments.

The invention also provides a preparation method of the beta-amino nitrile compound with high enantioselectivity, which has the advantages of simple operation, easily obtained raw material reagent, mild condition, green and environment-friendly reaction system and easy separation and purification of products, and is suitable for synthesizing various beta-amino nitrile compounds with high enantioselectivity, wherein amino introduced at beta-site has asymmetric stereocenter, and the chiral beta-amino nitrile compound can be further subjected to derivative conversion with stereospecific retention to synthesize other important chiral amine compounds. In addition, gram-scale experiments prove that the method is applicable to large-scale industrial production, and can efficiently prepare the high-purity chiral beta-aminonitrile compound.

Drawings

FIG. 1 shows the preparation of chiral β -aminonitrile 2a from example 1¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 2 shows the preparation of chiral β -aminonitrile 2a from example 1¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 3 is a high performance liquid chromatogram of a racemic product of example 1 of the present invention;

FIG. 4 is a high performance liquid chromatogram of chiral β -aminonitrile 2a prepared in example 1 of the present invention;

FIG. 5 shows the preparation of chiral β -aminonitrile 2c from example 3¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 6 shows chiral β -aminonitrile 2c prepared in example 3¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 7 is a high performance liquid chromatogram of a racemic product of example 3 of the present invention;

FIG. 8 is a high performance liquid chromatogram of chiral β -aminonitrile 2c prepared in example 3 of the present invention;

FIG. 9 is a high performance liquid chromatogram of a racemic product of example 6 according to the present invention;

FIG. 10 is a high performance liquid chromatogram of chiral β -aminonitrile 2f prepared in example 6 of the present invention;

FIG. 11 is a diagram of chiral β -aminonitrile 2k prepared in example 11¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 12 shows chiral β -aminonitrile 2k prepared in example 11¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 13 shows chiral β -aminonitrile 2k prepared in example 11¹⁹Nuclear magnetic resonance spectrum of F-NMR;

FIG. 14 is a high performance liquid chromatogram of a racemic product of example 11 of the present invention;

FIG. 15 is a high performance liquid chromatogram of chiral β -aminonitrile 2k prepared in example 11 of the present invention.

FIG. 16 shows chiral β -aminonitrile 2m prepared in example 13¹Nuclear magnetic resonance spectrum of H-NMR.

FIG. 17 shows chiral β -aminonitrile 2m prepared in example 13¹³Nuclear magnetic resonance spectrum of C-NMR.

FIG. 18 is a high performance liquid chromatogram of a racemic product of example 13 of the present invention.

FIG. 19 is a high performance liquid chromatogram of chiral β -aminonitrile 2m prepared in example 13 of the present invention.

Detailed Description

The invention firstly provides a beta-amino nitrile compound, which has a structural general formula shown as a formula I or a formula II:

in the formula I, R¹is-H, -CH₃、-OCH₃、-SCH₃、-OPh、-Ph、-F、-Cl、-Br； R²Is selected from benzyl;

R³selected from benzyl,

In the formula II, X is selected from O or S.

Preferably, the beta-aminonitrile compound has a structure represented by 2a to 2 p:

the invention also provides a preparation method of the beta-aminonitrile compound, which comprises the following steps:

adding a catalyst, a chiral diphosphine ligand and a solvent into a reaction vessel under the protection of nitrogen, stirring at room temperature, preferably for 5-10min, more preferably for 5min, then adding a hydroxylamine derivative, continuously stirring, preferably for 2-5min, more preferably for 3min, then adding a functionalized cinnamonitrile derivative, preferably stirring for 5min, finally adding a hydrosilane, reacting, preferably at room temperature, detecting the reaction completion by TLC, extracting, combining organic phases, drying with anhydrous sodium sulfate, performing suction filtration, removing the organic solvent by reduced pressure distillation, and finally performing silica gel column chromatography to obtain the chiral beta-aminonitrile compound.

According to the invention, the catalyst is preferably anhydrous copper acetate; the chiral ligand is preferably (S, S) -Ph-BPE; the solvent is preferably dried tetrahydrofuran, dioxane or toluene; the hydrosilane is preferably tetramethyldisiloxane, diethoxymethylhydrosilane or dimethoxymethylhydrosilane;

according to the invention, said cinnamonitrile derivatives can be prepared and synthesized according to the methods known in the art, in particular according to the literature (j.am. chem. soc.2015,137, 10177). The cinnamonitrile derivative is preferably trans-cinnamonitrile, 2-methylcinnamonitrile, 3-methoxycinnamonitrile, 4-methylthiocinnamonitrile, 4-phenylcinnamonitrile, 4-acetoxycinnamonitrile, 3- (4-fluoro-3-phenoxyphenyl) acrylonitrile, 3-fluorocinnamonitrile, 2-chlorocinnamonitrile, 2-bromocinnamonitrile, 3-trifluoromethoxy-cinnamonitrile, or 3-trifluoromethyl-cinnamonitrile.

The hydroxylamine derivative is preferably oxygen-benzoyl-nitrogen, nitrogen-dibenzylhydroxylamine, morpholino benzoate, thioequilin benzoate, oxygen-benzoyl-nitrogen-benzyl-nitrogen- (4-trifluoromethylbenzyl) hydroxylamine or oxygen-benzoyl-nitrogen-benzyl-nitrogen- (4-methoxybenzyl) hydroxylamine.

The hydrosilane is preferably Tetramethyldisiloxane (TMDS), Diethoxymethylhydrosilane (DEMS) or Dimethoxymethylhydrosilane (DMMS).

The molar ratio of the catalyst, the ligand (S, S) -Ph-BPE, the hydrosilane, the cinnamonitrile derivative and the hydroxylamine derivative is preferably 0.5: 0.5: 3.0: 1.0: 1.2.

according to the invention, the method is that a copper acetate catalyst and a chiral ligand (S, S) -Ph-BPE generate a chiral copper complex, and the chiral copper complex is reacted with cinnamonitrile and a hydroxylamine derivative under the action of hydrosilane to realize asymmetric conjugate addition reaction to obtain the beta-aminonitrile compound with high stereoselectivity. The chiral beta-amino nitrile compound has high regioselectivity and enantioselectivity, and the chiral center is positioned at the beta-position of-CN. The high performance liquid chromatography experiment proves that the ee value can reach 99 percent at most.

The present invention is further illustrated by reference to the following specific examples, in which other materials are commercially available.