CN113214158A - Preparation method of 2-trifluoromethyl imidazoline compound - Google Patents

Abstract

The invention discloses a preparation method of a 2-trifluoromethyl imidazoline compound, which comprises the following steps: adding N-iodosuccinimide, a 4A molecular sieve, trifluoroethylimidoyl chloride and allyl amine into an organic solvent, reacting at room temperature for 1-2 hours completely, and performing post-treatment to obtain the 2-trifluoromethyl imidazoline compound. The preparation method is simple to operate, the initial raw materials are cheap and easy to obtain, the reaction conditions are mild, the reaction time is short, the reaction does not need to be operated under the anhydrous and anaerobic conditions, heavy metals are not used as catalysts, the reaction can be expanded to gram level, imidazoline compounds with trifluoromethyl groups, which are variously substituted at different positions, can be synthesized through substrate design, and the applicability of the method is expanded while the operation is convenient.

Description

Preparation method of 2-trifluoromethyl imidazoline compound

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 2-trifluoromethyl imidazoline compound.

Background

Imidazoline compounds are important five-membered nitrogen-containing heterocycles with a wide range of biological and pharmaceutical activities, such as anti-cancer, anti-inflammatory, anti-diabetic and anti-hypertensive activities (j.med.chem.2009,52,1302). Some imidazoline structures can also be used as synthesis intermediates, organic adjuvants, and chiral ligands (org. lett.2020,22,2868). Therefore, many synthetic methods have been developed to construct such important nitrogen-containing heterocyclic compounds.

The traditional methods for preparing imidazolines reported in the literature today are the Heine reaction and related methods derived from the Heine reaction. These methods have the disadvantages of various synthetic steps and low total reaction yield. In addition, efficient synthesis methods have not been widely reported for some specially functionalized imidazoline compounds, such as trifluoromethyl substituted imidazolines.

Based on the method, a method for synthesizing 2-trifluoromethyl imidazoline simply and efficiently by using allyl amine and trifluoroethylimidoyl chloride which are simple and easy to obtain as starting materials and performing iodo cyclization reaction promoted by N-iodo succinimide is developed.

Disclosure of Invention

The invention provides a preparation method of a 2-trifluoromethyl imidazoline compound, which has the advantages of simple steps, cheap and easily-obtained starting raw materials, mild reaction conditions, short reaction time, no need of anhydrous and anaerobic conditions, avoidance of the use of toxic heavy metal catalysts and convenience in operation and application; the reaction can be easily expanded to gram-scale reaction, and the iodomethyl in the product is easy to be subjected to derivatization, so that the possibility is provided for future large-scale production and application.

A preparation method of a 2-trifluoromethyl imidazoline compound comprises the following steps: adding N-iodosuccinimide, a 4A molecular sieve, trifluoroethylimidoyl chloride and allyl amine into an organic solvent, reacting at room temperature for 1-2 hours completely, and performing post-treatment to obtain the 2-trifluoromethyl imidazoline compound;

the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):

the allyl amine has a structure shown in formula (III):

the structure of the 2-trifluoromethyl imidazoline compound is shown as the formula (I):

in formulae (I) to (III), R¹Is a substituted or unsubstituted aryl group;

R²is H, C₁～C₄Alkyl, substituted or unsubstituted aryl;

at R¹Wherein the substituents on the aryl group are selected from C₁～C₄Alkyl radical, C₁～C₄Alkoxy, halogen or trifluoromethyl.

The equivalent of the N-iodosuccinimide is 1-3 equivalents;

R¹the substitution position of the upper aryl group can be ortho-position, para-position or meta-position.

The reaction formula is exemplified as follows:

during the reaction, firstly, the coupling reaction of trifluoroethylimidoyl chloride and allylamine is probably carried out to generate an amidine intermediate, then N-iodosuccinimide and a double bond are subjected to iodination reaction to obtain a ternary iodonium ion, and then intramolecular nucleophilic attack and deprotonation are carried out to obtain the final 2-trifluoromethyl imidazoline compound. The reaction may proceed by ionic processes.

In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding 2-trifluoromethyl imidazoline compound, wherein the column chromatography purification is a technical means commonly used in the field.

Preferably, R¹The substituted or unsubstituted phenyl is selected from methyl, methoxy, bromine or trifluoromethyl, and in this case, the aromatic amine and the trifluoroethylimidoyl chloride are easily obtained and the reaction yield is high.

Preferably, R²H, methyl, phenyl or naphthyl, in which case the allylamine is readily prepared and the reaction yields are high.

Preferably, the iodide is N-iodosuccinimide, which is used in the reaction at a high yield.

Preferably, the 4A molecular sieve is used as the additive, the molecular sieve is cheaper and commonly used, and the reaction yield is higher.

The allylamine is relatively easy to prepare, and is preferably used in excess of the p-trifluoroethylimidoyl chloride, and the molar ratio of trifluoroethylimidoyl chloride: allyl amine: n-iodosuccinimide is 1: 2-3: 1-3; as a further preference, the molar amount of trifluoroethylimidoyl chloride: allyl amine: n-iodosuccinimide ═ 1:2.5: 2.

In the present invention, the organic solvent capable of sufficiently dissolving the raw material can cause the reaction, but the difference in reaction efficiency is large, and the aprotic solvent is preferably an aprotic solvent which can effectively promote the reaction; preferably, the organic solvent is acetonitrile, DMSO or DMF; more preferably, the organic solvent is acetonitrile, in which case the starting materials are converted to the product in high conversion.

The amount of the organic solvent can be used for better dissolving the raw materials, and the amount of the organic solvent used for 1mmol of trifluoroethylimidoyl chloride is about 5-10 mL.

Preferably, the iodide is N-iodosuccinimide, and the reaction efficiency is high when the N-iodosuccinimide is used as an accelerator.

As a further preference, the 2-trifluoromethyl imidazoline compound is one of the compounds shown in the formula (I-1) and the formula (I-5):

in the preparation method, the aromatic amine, the individual allylamine and the N-iodosuccinimide are generally commercially available products and can be conveniently obtained from the market, and the trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.

Compared with the prior art, the invention has the beneficial effects that: the preparation method does not need anhydrous and anaerobic conditions, has room temperature reaction, high reaction efficiency, easy operation and simple and convenient post-treatment, and can expand the reaction to gram level; the reaction starting raw materials are cheap and easy to obtain, the designability of the reaction substrate is strong, the tolerance range of the substrate functional group is wide, different substituted imidazoline compounds can be designed and synthesized according to actual needs, and the practicability is strong.

Detailed Description

The invention is further described with reference to specific examples.

Examples 1 to 15

Adding N-iodosuccinimide, a 4A molecular sieve, trifluoroethylimidoyl chloride (II), allyl amine (III) and 2mL of an organic solvent into a 35mL Schlenk tube according to the raw material ratio of Table 1, mixing and stirring uniformly, reacting according to the reaction conditions of Table 2, filtering after the reaction is finished, mixing a sample with silica gel, and purifying by column chromatography to obtain a corresponding 2-trifluoromethyl imidazoline compound (I), wherein the reaction process is shown as the following formula:

TABLE 1 raw material addition amounts of examples 1 to 15

TABLE 2

In tables 1 and 2, T is the reaction temperature, T is the reaction time, Ph is phenyl, Me is methyl, SMe is methylthio, and T-Bu is tert-butyl.

Structure confirmation data of the compounds prepared in examples 1 to 5:

nuclear magnetic resonance of 2-trifluoromethylimidazoline Compound (I-1) prepared in example 1 (II-1)¹H NMR、¹³C NMR and¹⁹f NMR) the data were:

¹H NMR(400MHz,CDCl₃)δ7.22(s,4H),4.15(d,J＝17.1Hz,1H),3.96(d,J＝17.1Hz,1H),3.28(d,J＝10.7Hz,1H),3.21(d,J＝10.7Hz,1H),2.40(s,3H),1.47(s,3H).

¹³C{¹H}NMR(101MHz,CDCl₃)δ152.6(C-F,q,²J_C-F＝35.7Hz),139.5,131.0,130.1,129.9,117.2(C-F,q,¹J_C-F＝276.5Hz),67.8,65.4,24.6,21.1,15.8.

¹⁹F NMR(377MHz,CDCl₃)δ-65.8.

M.p.112.4-113.5℃

HRMS(ESI):[M+H]⁺Calcd.for C₁₃H₁₄F₃IN₂ 383.0227；Found 383.0236.

nuclear magnetic resonance of 2-trifluoromethylimidazoline Compound (I-2) prepared in example 2 ((II-2))¹H NMR、¹³C NMR and¹⁹f NMR) the data were:

¹H NMR(400MHz,CDCl₃)δ7.32(s,1H),7.14(t,J＝8.2Hz,1H),4.17(d,J＝16.7Hz,1H),3.92(d,J＝16.5Hz,1H),3.24(q,J＝10.7Hz,1H),1.45(s,2H)

¹³C{¹H}NMR(101MHz,CDCl₃)δ162.7(C-F,d,¹J_C-F＝250.1Hz),152.1(C-F,q,²J_C-F＝35.5Hz),152.2,151.9,132.4(C-F,d,³J_C-F＝8.8Hz),130.4,117.4(C-F,q,¹J_C-F＝286.2Hz),117.2,116.2(C-F,q,²J_C-F＝22.7Hz),67.4,66.7,24.6,15.7.

¹⁹F NMR(377MHz,CDCl₃)δ-111.3,-65.8.

HRMS(ESI):[M+H]⁺Calcd.for C₁₂H₁₁F₄IN₂ 386.9976；Found 386.9984.

nuclear magnetic resonance of 2-trifluoromethylimidazoline Compound (I-3) prepared in example 3 ((II-3))¹H NMR、¹³C NMR and¹⁹f NMR) the data were:

¹H NMR(400MHz,CDCl₃)δ7.71(d,J＝8.4Hz,2H),7.44(d,J＝8.2Hz,2H),4.18(d,J＝17.8Hz,1H),3.93(d,J＝17.7Hz,1H),3.23(q,J＝10.8Hz,1H),1.45(s,3H).

¹³C{¹H}NMR(101MHz,CDCl₃)δ151.7(C-F,q,²J_C-F＝35.7Hz),138.2,131.1(C-F,q,²J_C-F＝33.0Hz),130.7,126.4,123.6(C-F,q,¹J_C-F＝272.3Hz),117.4(C-F,q,¹J_C-F＝275.7Hz),67.8,66.9,24.6,15.5.

¹⁹F NMR(377MHz,CDCl₃)δ-62.7,-65.5.

M.p.102.4–104.3℃

HRMS(ESI):[M+H]⁺Calcd.for C₁₃H₁₁F₆IN₂ 436.9944；Found 436.9950.

nuclear magnetic resonance of 2-trifluoromethylimidazoline Compound (I-4) prepared in example 4 (II)¹H NMR、¹³C NMR and¹⁹f NMR) the data were:

¹H NMR(400MHz,CDCl₃)δ7.28–6.86(m,4H),4.12(d,J＝17.2Hz,1H),3.86(d,J＝20.6Hz,4H),3.25(d,J＝10.6Hz,1H),3.17(d,J＝10.5Hz,1H),1.41(s,3H).

¹³C{¹H}NMR(101MHz,CDCl₃)δ157.8(C-F,q,²J_C-F＝37.3Hz),130.2,130.1,129.1,115.7(C-F,q,¹J_C-F＝287.7Hz),114.9,113.4,53.1,44.2,20.5,9.7.

¹⁹F NMR(377MHz,CDCl₃)δ-75.6.

HRMS(ESI):[M+H]⁺Calcd.for C₁₁H₁₀F₃IN₂ 369.0070；Found 369.0068.

nuclear magnetic resonance of 2-trifluoromethylimidazoline Compound (I-5) prepared in example 5 (II)¹H NMR、¹³C NMR and¹⁹f NMR) the data were:

¹H NMR(400MHz,CDCl₃)δ7.44–7.17(m,5H),6.96(d,J＝8.1Hz,2H),6.68(d,J＝7.9Hz,2H),4.62(d,J＝17.9Hz,1H),4.46(d,J＝18.3Hz,1H),3.72(q,J＝10.6Hz,2H),2.27(s,3H).

¹³C{¹H}NMR(101MHz,CDCl₃)δ152.4(C-F,q,²J_C-F＝35.3Hz),140.4,138.8,131.6,129.8,129.4,128.7,128.5,127.0,117.6(C-F,q,¹J_C-F＝275.7Hz),71.9,69.6,21.1,13.3.

¹⁹F NMR(377MHz,CDCl₃)δ-65.5.

M.p.118.3–119.2℃.

HRMS(ESI):[M+H]⁺Calcd.for C₁₈H₁₆F₃IN₂ 445.0383；Found 445.0390.

Claims (8)

1. a preparation method of a 2-trifluoromethyl imidazoline compound is characterized by comprising the following steps: adding an iodide, an additive, trifluoroethylimidoyl chloride and allyl amine into an organic solvent, reacting at room temperature for 1-2 hours, and performing post-treatment to obtain the 2-trifluoromethyl imidazoline compound;

the structure of the trifluoroethylimidoyl chloride is shown as a formula (II):

the allyl amine has a structure shown in formula (III):

the structure of the 2-trifluoromethyl imidazoline compound is shown as the formula (I):

in formulae (I) to (III), R¹Is a substituted or unsubstituted aryl group;

R²is H, C₁～C₄Alkyl, substituted or unsubstituted aryl;

at R¹Wherein the substituents on the aryl group are selected from C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio, halogen or trifluoromethyl;

at R²In (1), the substituent on the aryl group is halogen.

2. The method for producing 2-trifluoromethylimidazoline compound according to claim 1, wherein R is¹Is substituted or unsubstituted phenyl;

the substituent on the phenyl is selected from methyl, methoxy, bromine or trifluoromethyl.

3. The method for producing 2-trifluoromethylimidazoline compound according to claim 1, wherein R is²Is H, methyl, substituted or unsubstituted phenyl or naphthyl;

the substituent on the phenyl group is Cl.

4. The method for producing a 2-trifluoromethylimidazoline compound according to claim 1, wherein the molar amount of trifluoroethylimidoyl chloride: allyl amine: the iodide is 1:2 to 3:1 to 3.

5. The method for preparing 2-trifluoromethylimidazoline compound according to claim 1, wherein the organic solvent is acetonitrile.

6. The method for preparing 2-trifluoromethylimidazoline compound according to claim 1, wherein the iodide is N-iodosuccinimide.

7. The method for preparing 2-trifluoromethyl imidazoline compound according to claim 1, wherein the additive is 4A molecular sieve.

8. The method for preparing a 2-trifluoromethylimidazoline compound according to claim 1, wherein the 2-trifluoromethylimidazoline compound is one of compounds represented by formula (I-1) to formula (I-5):