CN111978194B - Preparation method of aryl acetamide compound - Google Patents
Preparation method of aryl acetamide compound Download PDFInfo
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- CN111978194B CN111978194B CN202010822636.XA CN202010822636A CN111978194B CN 111978194 B CN111978194 B CN 111978194B CN 202010822636 A CN202010822636 A CN 202010822636A CN 111978194 B CN111978194 B CN 111978194B
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of an aryl acetamide compound, which comprises the following steps: adding a palladium catalyst, a ligand, benzyl formate, tertiary amine and trifluoroacetic anhydride into an organic solvent, reacting for 24 hours at 130 ℃, and after the reaction is completed, carrying out post-treatment to obtain the aryl acetamide compound. The preparation method is easy to operate, the post-treatment is simple and convenient, the initial raw materials for the reaction are cheap and easy to obtain, benzyl formate is used as a carbon monoxide source and a reactant, tertiary amine is used as an amine source, the substrate designability is strong, the tolerance range of a substrate functional group is wide, and the reaction efficiency is high. It is worth noting that no additional oxidant is needed for C-N bond breakage of tertiary amine in the reaction, and a plurality of aryl acetamide compounds can be synthesized according to actual needs, so that the practicability is high.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an aryl acetamide compound.
Background
Amide compounds are a very important class of backbone molecules present in a variety of natural products, drugs and functional molecules (chem. Rev.1997,97, 2243-2266). Amide chemistry is an important component of organic chemistry, and functionalization of amide C-N bonds is ubiquitous in the synthesis of peptides, polymers, natural products, pesticides, advanced materials, and has important significance in organic synthesis (chem. Soc. Rev.2016,45, 1257-1272). Aryl acetamides, which are one of the amides, have attracted considerable attention due to their excellent physiological and pharmacological activities (chem. Rev.2010,110, 1082-1146).
The method for synthesizing the aryl acetamide compound reported in the literature is mainly to directly obtain the aryl acetamide compound by amidation reaction of phenylacetic acid and derivatives thereof. Transition metal catalyzed carbonylation reactions have become an alternative strategy to amide synthesis in recent years, and have attracted much attention. Such reactions mostly use primary and secondary amines as common amine sources. However, C-N bond activation of tertiary amines remains a significant challenge compared to primary and secondary amines. Few reports have been made up to date on carbonylation reactions involving C-N bond cleavage of tertiary amines, and although such reactions provide an efficient route to amide synthesis, they suffer from disadvantages such as excessive amounts of oxidizing agent, explosive CO/O under certain reaction conditions 2 Mixtures and the like. Therefore, the method has great development potential for the development and application of the C-N bond breakage of the tertiary amine in the reaction of synthesizing the aryl acetamide by carbonylation, and needs to be deeply researched.
Based on the above, we developed a method for efficiently synthesizing aryl acetamide compound by using cheap and easily available benzyl formate and tertiary amine as starting materials and by transition metal catalyzed carbonylation reaction.
Disclosure of Invention
The invention provides a preparation method of aryl acetamide compound, which takes benzyl formate as a carbon monoxide source and a reactant, takes tertiary amine as an amine source, has simple steps, cheap and easily obtained reaction raw materials, can be compatible with various functional groups, and has good reaction applicability. It is worth noting that the C-N bond of the tertiary amine is broken in the reaction without additional oxidant, and provides a new direction for the synthesis of the aryl acetamide compound.
A method for preparing an aryl acetamide compound, comprising the steps of: adding a palladium catalyst, a ligand, trifluoroacetic anhydride, benzyl formate and tertiary amine into an organic solvent, reacting for 20-30 hours at 120-140 ℃, and after the reaction is completed, carrying out post-treatment to obtain the aryl acetamide compound;
the structure of the benzyl formate is shown as a formula (II):
the structure of the tertiary amine is shown as the formula (III):
the structure of the aryl acetamide compound is shown as the formula (I):
in the formulas (I) to (III), ar is substituted or unsubstituted aryl, and the substituent on the aryl is selected from C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy, trifluoromethyl, -CN, or halogen;
R 1 ，R 2 ，R 3 independently is C 2 -C 5 An alkyl group.
The palladium catalyst comprises the following components: ligand: trifluoroacetic anhydride = 0.02-0.05.
The substitution position on the aryl group of Ar may be ortho, para or meta.
The reaction formula is as follows:
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 aryl acetamide compound, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, the aryl group is phenyl, furyl, naphthyl or thienyl; and the substituent on the aryl is selected from ethyl, isopropyl, tertiary butyl, -CN, cl, methoxy or trifluoromethyl, and in this case, the benzyl formate is easily obtained and the yield of the reaction is high.
Preferably, R 1 ，R 2 ，R 3 N-ethyl, n-propyl, isopropyl or n-pentyl, in which case the tertiary amine is readily available and the yield of the reaction is high.
The formic acid and benzyl alcohol used to prepare benzyl formate are relatively inexpensive, widely occurring in nature, in excess relative to the amount of tertiary amine used, and preferably, benzyl formate: tertiary amine: palladium catalyst = 1; as a further preference, benzyl formate: tertiary amine: palladium catalyst = 1.
Preferably, the reaction time is 24 hours, and if the reaction time is too long, the reaction cost is increased, and conversely, it is difficult to ensure the completion of the reaction.
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, tetrahydrofuran or dioxane; as a further preference, the organic solvent is acetonitrile, in which case the various starting materials can be converted into the product with relatively high conversion.
The dosage of the organic solvent can be enough to dissolve the raw material well, and the dosage of the organic solvent used by 1mmol of benzyl formate is about 2-3 mL.
Preferably, the catalyst is palladium acetate, which is relatively inexpensive among many palladium catalysts, and the reaction efficiency is high when palladium acetate is used as the catalyst.
Further preferably, the arylacetamide compound is one of compounds represented by the following formulae (I-1) to (I-5):
the compounds represented by the formulae (I-1) to (I-5) are known compounds.
In the above preparation method, the formic acid, benzyl alcohol, tertiary amine, palladium acetate, bis (2-diphenylphosphinophenyl) ether and trifluoroacetic anhydride are generally commercially available products, and can be conveniently obtained from the market.
Compared with the prior art, the invention has the beneficial effects that: the preparation method is easy to operate, simple and convenient in post-treatment, cheap and easily available in reaction starting raw materials, strong in substrate designability, wide in substrate functional group tolerance range and high in reaction efficiency, and benzyl formate is used as a carbon monoxide source and a reactant, and tertiary amine is used as an amine source. It is worth noting that no additional oxidant is needed for C-N bond breakage of tertiary amine in the reaction, and a plurality of aryl acetamide compounds can be synthesized according to actual needs, so that the practicability is high.
Detailed Description
The invention is further described with reference to specific examples.
Adding palladium acetate, bis (2-diphenylphosphinophenyl) ether, trifluoroacetic anhydride, benzyl formate (II), tertiary amine (III) and 2mL of an organic solvent into a 15mL sealed tube according to the raw material ratio of Table 1, uniformly mixing and stirring, reacting for 24 hours according to the reaction conditions of Table 2, filtering, mixing a silica gel sample, and purifying by column chromatography to obtain the corresponding aryl acetamide 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, et is ethyl, OMe is methoxy, T-Bu is T-butyl, and i-Pr is isopropyl.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of arylacetamide Compound (I-1) obtained in example 1: ( 1 H NMR and 13 c NMR) the data were:
1 H NMR(400MHz,CDCl 3 )δ7.17(s,4H),3.66(s,2H),3.38(q,J＝7.1Hz,2H),3.29(q,J＝7.1Hz,2H),2.87(hept,J＝6.9Hz,1H),1.23(d,J＝6.9Hz,6H),1.10(dt,J＝14.6,7.1Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ170.3,147.2,132.7,128.5,126.6,42.3,40.4,40.1,33.7,24.0,14.2,12.9.
nuclear magnetic resonance of arylacetamide Compound (I-2) obtained in example 2: ( 1 H NMR and 13 c NMR) the data were:
1 H NMR(400MHz,CDCl 3 )δ7.17(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,2H),3.79(s,3H),3.63(s,2H),3.38(q,J＝7.1Hz,2H),3.30(q,J＝7.1Hz,2H),1.10(dt,J＝10.4,7.1Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ170.6,158.4,129.6,127.5,114.0,55.2,42.3,40.2,39.9,14.2,12.9.
nuclear magnetic resonance of arylacetamide Compound (I-3) obtained in example 3: ( 1 H NMR and 13 c NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝8.1Hz,2H),7.38(d,J＝8.0Hz,2H),3.74(s,2H),3.40(q,J＝7.1Hz,2H),3.32(q,J＝7.2Hz,2H),1.14(dd,J＝13.5,7.1Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ169.2,139.6,129.2,129.0(d,J＝32.9Hz),125.4(d,J＝3.6Hz),124.2(q,J＝271.9Hz),42.3,40.3,40.2,14.2,12.8.
nuclear magnetic resonance of arylacetamide Compound (I-4) obtained in example 4: ( 1 H NMR and 13 c NMR) the data were:
1 H NMR(400MHz,CDCl 3 )δ7.35(d,J＝1.3Hz,1H),6.34-6.31(m,1H),6.19(d,J＝3.1Hz,1H),3.72(s,2H),3.38(dq,J＝11.9,7.1Hz,4H),1.14(dd,J＝13.4,7.0Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ167.8,149.3,141.6,110.5,107.4,42.4,40.3,33.9,14.2,12.9.
nuclear magnetic resonance of Compound 2 (I-5) prepared in example 5: ( 1 H NMR and 13 c NMR) the data detected were:
1 H NMR(400MHz,CDCl 3 )δ7.32-7.18(m,5H),4.00-3.89(m,1H),3.67(s,2H),3.35(s,1H),1.41(dd,J＝6.7,2.0Hz,6H),0.98(dd,J＝6.4,2.9Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ169.6,135.6,128.3,128.2,126.2,49.1,45.5,43.2,20.2.
Claims (5)
1. a method for preparing an aryl acetamide compound, comprising the steps of: adding a palladium catalyst, a ligand, benzyl formate, tertiary amine and trifluoroacetic anhydride into an organic solvent, reacting for 20-30 hours at 120-140 ℃, and performing post-treatment after complete reaction to obtain the aryl acetamide compound;
the structure of the benzyl formate is shown as a formula (II):
the structure of the tertiary amine is shown as the formula (III):
the structure of the aryl acetamide compound is shown as the formula (I):
in formulas (I) to (III), ar is substituted or unsubstituted aryl, and substituents on the aryl are selected from C 1 ～C 4 Alkyl radical, C 1 ～C 4 Alkoxy, trifluoromethyl, -CN, or halogen;
R 1 ，R 2 ，R 3 independently is C 2 -C 5 An alkyl group;
the organic solvent is acetonitrile;
the palladium catalyst is palladium acetate;
the ligand is bis (2-diphenylphosphinophenyl) ether.
2. The method for producing an arylacetamide compound according to claim 1, wherein the aryl group is a phenyl group or a naphthyl group;
the substituent on the aryl is selected from ethyl, isopropyl, tert-butyl, -CN, cl, methoxy or trifluoromethyl.
3. The method of claim 1, wherein R is selected from the group consisting of 1 ，R 2 ，R 3 Independently n-ethyl, n-propyl, isopropyl or n-pentyl.
4. The method for producing an arylacetamide compound according to claim 1, wherein the molar ratio of benzyl formate: tertiary amine: trifluoroacetic anhydride: palladium catalyst: ligand = 1.
5. The method for preparing an arylacetamide compound according to claim 1, wherein the arylacetamide compound is one of compounds represented by formula (I-1) -formula (I-3) and formula (I-5):
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Non-Patent Citations (5)
| Title |
|---|
| 1-Arylvinyl formats: A New CO Source and Ketone Source in Carbonylative Synthesis of Chalcone Derivatives;Xinxin Qi等;《ChemCatChem》;20191231;第11卷;第5252-5255页 * |
| Carbonylative transformation of benzyl formates into alkyl 2-arylacetates in organic carbonates;Xinxin Qi等;《Org.Chem.Front.》;20190815;第6卷;第3397-3400页 * |
| HMF and furfural: Promising platform molecules in rhodium-catalyzed carbonylation reactions for the synthesis of furfuryl esters and tertiary amides;Xinxin Qi等;《Journal of Catalysis》;20191122;第381卷;第215-221页 * |
| Palladium-catalyzed carbonylative synthesis of arylacetamides from benzyl formates and tertiary amines;Ming Lai等;《Org.Chem.Front.》;20200921;第7卷;第3406-3410页 * |
| Palladium-Catalyzed Carbonylative Synthesis of Benzyl Benzoates Employing Benzyl Formates as Both CO Surrogates and Benzyl Alcohol Sources;Ming Lai等;《Eur.J.Org.Chem.》;20191231;第3776-3778页 * |
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