CN105294601A - Thioamide compound and compounding method thereof - Google Patents

Thioamide compound and compounding method thereof Download PDF

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CN105294601A
CN105294601A CN201510725463.9A CN201510725463A CN105294601A CN 105294601 A CN105294601 A CN 105294601A CN 201510725463 A CN201510725463 A CN 201510725463A CN 105294601 A CN105294601 A CN 105294601A
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phenyl
reaction
aldehyde
hydrogen
formyl radical
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CN105294601B (en
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姜雪峰
魏建朋
李一鸣
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East China Normal University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
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    • C07C327/00—Thiocarboxylic acids
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    • C07C327/46—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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Abstract

The invention discloses a compounding method for a thioamide compound shown as formula (II). The compounding method comprises the following steps: by taking aldehyde and formyl aliphatic amine as reacting raw materials and taking Na2S.9H2O as a sulfuration reagent, reacting in a water phase under an effect of an oxidizing agent, thereby acquiring the thioamide compound. The compounding method provided by the invention has the advantages that the raw materials are low in cost and are easily acquired, the solvents are green and environment-friendly, the reaction operation is simple, the condition is mild, the substrate is wide in universality, the yield is higher, the functional group tolerance is excellent, the thioamide modification for natural aldehyde and biological active molecule is successively realized, and a method for efficiently constructing the thioamide compound is supplied to the medicinal chemical and biologic orthogonal chemical research.

Description

Thioamide analog compound and synthetic method thereof
Technical field
The invention belongs to the synthesis of organic compound technique and applied technical field, be specifically related to thioamide analog compound and synthetic method thereof.
Background technology
Thioamide analog compound is the very important compound of a class, is widely used as various kinds of drug and bioactive molecules, shown in (i) ~ formula (iii).Therefore, from simple, the commercial compound that can obtain in a large number of some structures, build thioamide analog compound and seem particularly important.
Containing the medicine fractionated molecule of sulfo-amide structure
The traditional method of synthesis thioamide analog compound is mainly prepared by acid amides and lawesson reagent or thiophosphoric anhydride.In these class methods, the lawesson reagent used is unstable, and price costly, Atom economy is low, and stink is large, and all has injury in various degree to environment and human body, required acid amides will pass through carboxylic acid (or acyl chlorides) and amine condensation preparation in advance, and step economy is low.In recent years, develop and utilized Willgerodt-Kindler to react the method preparing thioamide analog compound, the method utilizes sulphur simple substance as sulphur source, aryl aldehyde, aryl groups per alkyl group ketone, aryl ethane, benzylamine, Arylacetic acids etc. synthesize thioamide analog compound as raw material, compare traditional method, the method increase atom utilization and step economy, but substrate universality is wideless, part substrate reactions condition is harsh, temperature of reaction is up to 320 DEG C, many raw materials are not easy to obtain, and the use of organic solvent also limit its practicality.Many deficiencies constrain the profound level application of these class methods in technical study and field of pharmaceutical chemistry research above.
" Green Chemistry ", as one of the major objective of the chemical developer of 21 century, requiring that the researcher being engaged in chemistry effectively should utilize raw material when developing chemical reaction, avoiding the use of harmful reagent and solvent.Given this, the method developing a kind of green high-efficient synthesis thioamides becomes the vertical topic foundation of the present invention and technical problem to be solved.
Summary of the invention
Instant invention overcomes the above-mentioned defect of prior art, propose a kind of method of efficient structure thioamide analog compound innovatively.Method of the present invention uses aldehyde compound and formyl radical aliphatic amide to be raw material, with Na 2s9H 2o is sulfiding reagent, under oxygenant effect, using water as reaction solvent, prepares such as formula the thioamide analog compound shown in (II).Synthetic method of the present invention, cheaper starting materials is easy to get, solvent environmental protection, operation is simple, mild condition, and substrate universality is wide, productive rate is high, can compatible alcoholic extract hydroxyl group, phenolic hydroxyl group, allyl group, thiazolinyl, electron-donating group, electron-withdrawing group and steric group, and stereospecificity keeps.
The present invention proposes a kind of synthetic method of thioamide analog compound, wherein, with aldehyde and formyl radical aliphatic amide for reaction raw materials, with Na 2s9H 2o is sulfiding reagent, and under the effect of oxygenant (comprising peroxygen oxidising agent), under 25 ~ 100 DEG C of conditions, in reaction solvent, reaction obtains such as formula the thioamide analog compound shown in (II) for 3 ~ 24 hours; Described reaction process is as shown in following reaction formula (a).
In described reaction formula (a), R is alkyl or aryl; R 1/ R 2alkyl, containing arylalkyl or hydrogen.In the present invention, R, R 1/ R 2include but are not limited to above-mentioned group.
Wherein, in described reaction formula (a), R is isobutyl-, 2-phenylethyl, benzyl, cyclohexyl, 2, 6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1, 5 dimethyl-4-thiazolinyl hexyls, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-p-methoxy-phenyl, 3, 4, 5-trimethoxyphenyl, 3-trifluoromethyl, 4-trifluoromethyl, 4-chloro-phenyl-, 4-bromophenyl, 4-hydroxy phenyl, 2-hydroxy phenyl, 2-naphthyl, 2-thiophene, 2-pyridine, 2-cumarone, cholesterol derivative or estrone derivative, R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen, propyl group/hydrogen, benzyl/hydrogen, allyl group/hydrogen,
In the present invention, described temperature of reaction is 25 ~ 100 DEG C, preferably, carries out under 100 DEG C of conditions.
In the present invention, described starting raw material is such as formula the aldehyde compound (substrate 1) shown in (I) and sulfiding reagent Na 2s9H 2the consumption mol ratio of O is 1:1 ~ 7.Preferably, both consumption mol ratios are 1:3.5.
In the present invention, described starting raw material is 1:1 ~ 10 such as formula the aldehyde compound shown in (I) and formyl radical aliphatic amide (substrate 2) consumption mol ratio.Preferably, both consumption mol ratios are 1:5.
In the present invention; described oxygenant is selected from 1; 4-benzoquinones, dibenzoyl peroxide, Potassium Persulphate, oxygen, metachloroperbenzoic acid, iodobenzene diacetate, iron nitrate, peroxide list potassium sulfonate etc.; preferably; described oxygenant is dibenzoyl peroxide or Potassium Persulphate, and the consumption mol ratio such as formula the raw material aldehyde shown in (I) and described oxygenant is 1:1 ~ 5.When described oxygenant is dibenzoyl peroxide, preferably, the consumption mol ratio such as formula the raw material aldehyde shown in (I) and described dibenzoyl peroxide is 1:2.5.When described oxygenant is Potassium Persulphate, preferably, the consumption mol ratio such as formula the raw material aldehyde shown in (I) and described Potassium Persulphate is 1:1.8.
The acting as of oxygenant of the present invention impels formyl radical aliphatic amide to produce amine free radical, and is oxidized final thioamides free radical and obtains final thioamide product.
In the present invention, in described synthetic method, can further include additive.Described additive is pyridine, triethylamine, tetrabutylammonium chloride, Tetrabutyl amonium bromide or tetrabutylammonium iodide, and preferably, described additive is pyridine.The molar weight of described additive mostly is 5 times such as formula the aldehyde shown in (I) most; Preferably, described additive molar weight for such as formula the aldehyde shown in (I) 5 times.
Acting as of additive of the present invention increases aldehyde (substrate 1) solubleness in a solvent.
In the present invention, described reaction solvent is that DMF, methyl-sulphoxide, N,N-dimethylacetamide, N-Methyl pyrrolidone, Nitromethane 99Min., ethylene glycol, acetonitrile, Isosorbide-5-Nitrae-dioxane, p-Xylol or water are a kind of arbitrarily.Preferably, described solvent is water.
In synthetic method of the present invention; when substrate aldehyde and formyl radical aliphatic amide are liquid; said method comprising the steps of: first in reaction vessel, add sulfiding reagent; then add in reaction vessel by being dissolved in the substrate aldehyde of solvent, formyl radical aliphatic amide and additive; finally add oxygenant; react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide analog compound shown in formula (II).
In synthetic method of the present invention, when aldehyde be liquid, formyl radical aliphatic amide be solid time, said method comprising the steps of: the formyl radical aliphatic amide first adding sulfiding reagent and solid in reaction vessel, then the substrate aldehyde and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant, react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide compound shown in formula (II);
In synthetic method of the present invention, when aldehyde be solid, formyl radical aliphatic amide be liquid time, said method comprising the steps of: the aldehyde first adding sulfiding reagent, solid in reaction vessel, then the formyl radical aliphatic amide and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant, react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide compound shown in formula (II);
In synthetic method of the present invention; when aldehyde and formyl radical aliphatic amide are solid; said method comprising the steps of: first in reaction vessel, add sulfiding reagent, aldehyde and formyl radical aliphatic amide; then the additive being dissolved in solvent is added in reaction vessel; finally add oxygenant; react 3-24 hour under 25 ~ 100 DEG C of conditions after, obtain the thioamide compound shown in formula (II).
In a specific examples, building-up reactions of the present invention is in reaction flask A:
(1) when substrate aldehyde and formyl radical aliphatic amide are liquid, then in reaction vessel, sulfiding reagent Na is added 2s9H 2o (Xmmol), is then dissolved in solvent H by substrate aldehyde (formula I, Ymmol), formyl radical aliphatic amide (Zmmol) and additive pyridine (Wmmol) 2o (VmL) adds in reaction vessel, then adds oxygenant dibenzoyl peroxide (Ummol) or Potassium Persulphate (Smmol);
(2) when aldehyde be solid, formyl radical aliphatic amide be liquid time, then in reaction vessel, add sulfiding reagent Na 2s9H 2o (Xmmol), substrate aldehyde (formula I, Ymmol), is then dissolved in solvent H by formyl radical aliphatic amide (Zmmol) and additive pyridine (Wmmol) 2o (VmL) adds in reaction vessel, then adds oxygenant dibenzoyl peroxide (Ummol) or Potassium Persulphate (Smmol);
(3) when aldehyde be liquid, formyl radical aliphatic amide be solid time, then in reaction vessel, add sulfiding reagent Na 2s9H 2o (Xmmol), formyl radical aliphatic amide (Zmmol), is then dissolved in solvent H by substrate aldehyde (formula I, Ymmol) and additive pyridine (Wmmol) 2o (VmL) adds in reaction vessel, then adds oxygenant dibenzoyl peroxide (Ummol) or Potassium Persulphate (Smmol);
(4) when substrate aldehyde and formyl radical aliphatic amide are solid, then in reaction vessel, sulfiding reagent Na is added 2s9H 2o (Xmmol), substrate aldehyde (formula I, Ymmol), formyl radical aliphatic amide (Zmmol), is then dissolved in solvent H by additive pyridine (Wmmol) 2o (VmL) adds in reaction vessel, then adds oxygenant dibenzoyl peroxide (Ummol) or Potassium Persulphate (Smmol);
Reaction system stirs 3-24 hour at 60-100 DEG C; After thin-layer chromatography monitoring reaction terminates, reaction system is cooled to room temperature, in system, adds H 2o (10mL) dilutes, and with ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filters, concentrated, obtains target product formula II through column chromatography for separation;
The invention allows for according to the above-mentioned synthetic method of the present invention prepare such as formula the thioamide analog compound shown in (II),
Wherein, R is alkyl, aryl; R 1/ R 2alkyl, containing arylalkyl or hydrogen.
Preferably, R is isobutyl-, 2-phenylethyl, benzyl, cyclohexyl, 2, 6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1, 5 dimethyl-4-thiazolinyl hexyls, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-p-methoxy-phenyl, 3, 4, 5-trimethoxyphenyl, 3-trifluoromethyl, 4-trifluoromethyl, 4-chloro-phenyl-, 4-bromophenyl, 4-hydroxy phenyl, 2-hydroxy phenyl, 2-naphthyl, 2-thiophene, 2-pyridine, 2-cumarone, cholesterol derivative or estrone derivative, R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen, propyl group/hydrogen, benzyl/hydrogen, allyl group/hydrogen,
New compound prepared by the present invention, is characterized in that, its structural formula such as formula shown in (II),
Wherein, R is isobutyl-, cyclohexyl, 2,6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1,5 dimethyl-4-thiazolinyl hexyls, phenyl, 3-chloro-phenyl-, 3-bromophenyl, 2-cumarone, cholesterol derivative or estrone derivative;
R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen,
Preferably, described new thioamide analog compound comprises:
The advantage of synthetic method of the present invention comprises: each raw material used is industrialization commodity, simple and easy to get, wide material sources, and performance is highly stable, does not need special preservation condition; The present invention uses inorganic salt Na 2s9H 2o, as sulfiding reagent, has the characteristic that cost is low, productive rate is high, simple to operate, Atom economy is high, is applicable to industrialization scale operation completely; The solvent that synthetic method of the present invention adopts is pollution-free, and water especially can be adopted as reaction solvent, environmental protection, the aftertreatment of product is simple; Inventive substrate universality is wide, functional group tolerance is good, and the thioamidesization successfully achieving natural product aldehyde and bioactive molecules modifies (such as, embodiment 5,6,10,11,12,13,14,42,43), for pharmaceutical chemistry, bio-orthogonal chemical research provide the efficient method building thioamide analog compound.
Embodiment
In embodiment 1 ~ 13, in embodiment 15 ~ 42, solvent for use is water.
In embodiment 14 and embodiment 43, solvent for use is water: ethylene glycol=1:1 (volume ratio).
In embodiment 1 ~ 15, embodiment 17 ~ 19, embodiment 21, embodiment 23 ~ 24, in embodiment 41 ~ 43, Na used 2s9H 2o molar weight is 3.5 times of aldehyde; Oxygenant used is Potassium Persulphate, and molar weight is 1.8 times of aldehyde.The molar weight of formyl radical aliphatic amide used is 5 times of aldehyde.
In embodiment 16, embodiment 20, embodiment 22, embodiment 25, embodiment 27 ~ 32, in embodiment 37 ~ 40, Na used 2s9H 2o molar weight is 3.5 times of aldehyde; Oxygenant used is dibenzoyl peroxide, and molar weight is 2.5 times of aldehyde; The molar weight of formyl radical aliphatic amide used is 5 times of aldehyde.
In embodiment 26, in embodiment 33 ~ 36, Na used 2s9H 2o molar weight is 7 times of aldehyde; Oxygenant used is dibenzoyl peroxide, and mole dosage is 5 times of aldehyde; The molar weight of formyl radical aliphatic amide used is 10 times of aldehyde.
In embodiment 1 ~ 12, embodiment 14 ~ 23, embodiment 31, embodiment 35 ~ 36, in embodiment 41 ~ 43, temperature of reaction is 100 DEG C.
In embodiment 13, embodiment 24 ~ 30, embodiment 32 ~ 34, embodiment 37 ~ 40, temperature of reaction is 60 DEG C.
In embodiment 1 ~ 15, embodiment 17 ~ 19, embodiment 21, embodiment 23 ~ 24, in embodiment 41 ~ 43, with the addition of pyridine, and pyridine molar weight used is 5 times of aldehyde.
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.Data given by following examples comprise concrete operations and reaction conditions and product.Product purity is identified by nuclear-magnetism.
The building-up reactions of arylalkyl thioethers compound of the present invention, comprise the following steps: when substrate aldehyde and formyl radical aliphatic amide are liquid, first in reaction vessel, add sulfiding reagent, then add in reaction vessel by being dissolved in the substrate aldehyde of solvent, formyl radical aliphatic amide and additive, finally add oxygenant, react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide analog compound shown in formula (II); When aldehyde be liquid, formyl radical aliphatic amide be solid time, in reaction vessel, first add the formyl radical aliphatic amide of sulfiding reagent and solid, then the substrate aldehyde and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant, react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide compound shown in formula (II); When aldehyde be solid, formyl radical aliphatic amide be liquid time, in reaction vessel, first add the aldehyde of sulfiding reagent, solid, then the formyl radical aliphatic amide and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant, react after 3 ~ 24 hours under 25 ~ 100 DEG C of conditions, obtain the thioamide compound shown in formula (II); When aldehyde and formyl radical aliphatic amide are solid; first in reaction vessel, add sulfiding reagent, aldehyde and formyl radical aliphatic amide; then the additive being dissolved in solvent is added in reaction vessel; finally add oxygenant; react 3-24 hour under 25 ~ 100 DEG C of conditions after, obtain the thioamide compound shown in formula (II).The thioamide compound prepared of above-mentioned steps again through extraction, dry, filter, concentrated, column chromatography for separation obtains the object product of purifying.
Thioamide analog compound as shown in table 1, is and synthesizes by the inventive method the product obtained, and there is not yet open source literature and discloses these compounds.
The thioamide analog compound of table 1 synthetic method synthesis of the present invention
Embodiment 1
The synthesis of compound 2a:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by isovaleric aldehyde (0.3mmol; 25.8mg), N-formyl piperidine (1.5mmol, 169.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 8 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow liquid 2a (33.8mg through column chromatography for separation, 61%), R f=0.55 (PE:EA=10:1); 1hNMR (400MHz, CDCl 3) δ 4.38-4.25 (m, 2H), 3.76-3.68 (m, 2H), 2.80 (d, J=7.3Hz, 2H), 2.24-2.07 (m, 1H), 1.78-1.60 (m, 6H), 1.00 (d, J=6.7Hz, 6H) 13cNMR (100MHz, CDCl 3) δ 201.4,52.0,51.6,51.1,28.9,26.9,25.4,24.1,22.4; IR (film) 2937,2361,1487,1440,1265,1149,1079,1002,852cm -1; HRMS (EI) CalcdforC 10h 19nS185.1238, Found185.1235.
Embodiment 2
The synthesis of compound 2b:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by isovaleric aldehyde (0.3mmol; 25.8mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 9 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain weak yellow liquid 2b (32.0mg through column chromatography for separation, 57%), R f=0.6 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 4.44-4.25 (m, 2H), 3.86-3.62 (m, 6H), 2.76 (d, J=7.3Hz, 2H), 2.17-2.06 (m, 1H), 0.99 (d, J=6.7Hz, 6H); 13cNMR (100MHz, CDCl 3) δ 203.2,66.6,66.5,51.6,50.4,50.1,29.1,22.3; IR (film) 2961,2925,2866,1478,1431,1259,1115,1021,797cm -1; MS (EI) m/z (%) 187 (100), 144 (80), 86 (85).
Embodiment 3
The synthesis of compound 2c:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by 3-phenylpropion aldehyde (0.3mmol, 40.2mg), DMF (1.5mmol, 109.5mg), pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 8 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain orange liquid 2c (48.0mg through column chromatography for separation, 83%), R f=0.4 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.32-7.27 (m, 2H), 7.24-7.20 (m, 3H), 3.48 (s, 3H), 3.14 (s, 3H), 3.13-3.09 (m, 2H), 3.09-3.03 (m, 2H); 13cNMR (100MHz, CDCl 3) δ 203.1,140.6,128.5,128.4,126.4,44.9,44.6,41.5,35.7; IR (film) 3025,2963,1514,1496,1393,1260,1093,1017,798,700cm -1; MS (EI) m/z (%) 193 (100), 88 (90).
Embodiment 4
The synthesis of compound 2d:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by 3-phenylpropion aldehyde (0.3mmol; 40.2mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 3 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain orange liquid 2d (58.5mg through column chromatography for separation, 83%), R f=0.4 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.30-7.27 (m, 2H), 7.23-7.20 (m, 3H), 4.32-4.30 (m, 2H), 3.70-3.68 (m, 2H), 3.54-3.51 (m, 2H), 3.39-3.36 (m, 2H), 3.12-3.10 (m, 4H); 13cNMR (100MHz, CDCl 3) δ 202.6,140.1,128.5,128.5,126.5,66.3,66.0,50.0,49.8,44.1,35.7; IR (film) 3302,3060,3028,2962,2862,1531,1488,1453,1384,1261,1093,1027,943,802,767,695cm -1; MS (EI) m/z (%) 235 (45), 144 (100), 91 (60).
Embodiment 5
The synthesis of compound 2e:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by geranial (0.3mmol; 46.2mg), N-formyl radical-2-monoethanolamine (1.5mmol, 133.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 5 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid 2e (34.4mg through column chromatography for separation, 50%), R f=0.50 (PE:EA=1:1). 1hNMR (400MHz, CDCl 3) δ 7.72 (br, 1H), 5.10-5.07 (m, 1H), 3.94-3.83 (m, 4H), 2.70 (dd, J=13.2,6.1Hz, 1H), 2.41 (dd, J=13.1,8.5Hz, 1H), 2.20-2.12 (m, 1H), 2.08-1.94 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.27-1.14 (m, 2H), 0.92 (d, J=6.6Hz, 3H); 13cNMR (100MHz, CDCl 3) δ 205.7,131.6,124.2,60.6,54.9,47.8,36.5,33.5,25.7,25.4,18.9,17.7; IR (film) 3266,2957,2926,1534,1457,1404,1318,1052,718cm -1; HRMS (EI) CalcdforC 12h 23nOS229.1500, Found229.1501.
Embodiment 6
The synthesis of compound 2f:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by geranial (0.3mmol; 46.2mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 10 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain weak yellow liquid 2f (46.7mg through column chromatography for separation, 61%), R f=0.4 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 5.06 (t, J=7.0Hz, 1H), 4.36-4.34 (m, 2H), 3.86-3.65 (m, 6H), 2.86 (dd, J=13.4,6.2Hz, 1H), 2.73 (dd, J=13.4,8.5Hz, 1H), 2.09-1.92 (m, 3H), 1.66 (s, 3H), 1.59 (s, 3H), 1.51-1.39 (m, 1H), 1.34-1.25 (m, 1H), 0.98 (d, J=6.6Hz, 3H); 13cNMR (100MHz, CDCl 3) δ 203.1,131.7,124.2,66.6,66.5,50.4,50.2,50.1,36.7,33.1,25.7,25.3,19.2,17.7; IR (film) 2963,2906,1477,1432,1259,1084,1012,792.702cm -1; HRMS (EI) CalcdforC 14h 25nOS255.1657, Found255.1655.
Embodiment 7
The synthesis of compound 2g:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenylacetic aldehyde (0.3mmol; 36.0mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 9 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid 2g (30.6mg through column chromatography for separation, 46%), R f=0.35 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.31-7.17 (m, 5H), 4.33-4.27 (m, 4H), 3.71-3.66 (m, 2H), 3.60-3.54 (m, 2H), 3.36-3.30 (m, 2H); 13cNMR (100MHz, CDCl 3) δ 200.0,135.7,128.9,127.7,127.1,66.3,66.1,50.7,50.6,50.1; IR (film) 3407,3059,3026,2964,2855,1602,1487,1433,1296,1254,1109,1030,959,751,705cm -1; MS (EI) m/z (%) 221 (70), 130 (75), 91 (100).
Embodiment 8
The synthesis of compound 2h:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by hexahydrobenzaldehyde (0.3mmol; 33.7mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 4 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain faint yellow solid 2h (32.6mg through column chromatography for separation, 51%), R f=0.6 (PE:EA=10:1); 1hNMR (400MHz, CDCl 3) δ 4.45-4.30 (m, 2H), 3.92-3.64 (m, 6H), 2.69 (t, J=10.9Hz, 1H), 1.83-1.74 (m, 4H), 1.70-1.67 (m, 3H), 1.32-1.24 (m, 3H); 13cNMR (100MHz, CDCl 3) δ 209.2,66.7,66.6,50.0,49.5,47.3,33.2,26.1,25.6; IR (film) 2956,2925,2852,1462,1429,1261,1119,1030,797cm -1; MS (EI) m/z (%) 213 (80), 126 (25), 86 (100).
Embodiment 9
The synthesis of compound 2i:
Na is added in reaction tubes 2s9H 2o (1.05mmol; 252mg); N-formyl radical-2-phenyl-ethyl amine (1.5mmol; 223.5mg); by hexahydrobenzaldehyde (0.3mmol, 33.7mg), pyridine (1.5mmol; 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 8 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow liquid 2i (40.7mg through column chromatography for separation, 55%), R f=0.50 (PE:EA=10:1). 1hNMR (400MHz, CDCl 3) δ 7.37-7.17 (m, 5H), 7.12 (br, 1H), 3.95 (dd, J=12.5,6.8Hz, 2H), 2.98 (t, J=6.9Hz, 2H), 2.46-2.38 (m, 1H), 1.88-1.74 (m, 4H), 1.69-1.66 (m, 1H), 1.55-1.47 (m, 2H), 1.27-1.18 (m, 3H); 13cNMR (100MHz, CDCl 3) δ 210.4,138.3,128.8,128.7,126.8,55.0,46.3,33.7,32.8,25.9,25.6; IR (film) 3243,2928,2853,1524,1450,1280,1131,979,698cm -1; HRMS (EI) CalcdforC 15h 21nS247.1395, Found247.1392.
Embodiment 10
The synthesis of compound 2j:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by α-methyl-p-tert.-butyl phenylpropionaldehyde (0.3mmol; 61.3mg), N-formyl morpholine (1.5mmol, 172..5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 20 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain faint yellow solid 2j (59.5mg through column chromatography for separation, 65%), R f=0.3 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.28 (d, J=8.3Hz, 2H), 7.14 (d, J=8.3Hz, 2H), 4.82-4.74 (m, 1H), 3.88-3.82 (m, 1H), 3.73-3.69 (m, 1H), 3.57-3.53 (m, 1H), 3.48-3.39 (m, 3H), 3.35-3.28 (m, 1H), 3.09 (dd, J=13.1,8.9Hz, 1H), 2.83 (dd, J=13.1,5.6Hz, 1H), 2.66-2.60 (m, 1H), 1.34 (d, J=6.4Hz, 3H), 1.29 (s, 9H); 13cNMR (100MHz, CDCl 3) δ 208.8,149.5,136.6,128.8,125.2,66.3,65.9,50.3,49.8,43.8,43.6,34.3,31.3,22.2; IR (film) 3024,2862,1510,1471,1433,1274,1233,1113.1024,983,872,837,805cm -1; HRMS (EI) CalcdforC 18h 27nOS305.1813, Found305.1814.
Embodiment 11
The synthesis of compound 2k:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by α-methyl-p-tert.-butyl phenylpropionaldehyde (0.3mmol; 61.3mg), N-formyl piperidine (1.5mmol, 169.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 24 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid 2k (47.3mg through column chromatography for separation, 52%), R f=0.50 (PE:EA=10:1). 1hNMR (400MHz, CDCl 3) δ 7.27 (d, J=8.6Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 4.70-4.59 (m, 1H), 3.89-3.80 (m, 1H), 3.68-3.62 (m, 1H), 3.47-3.38 (m, 1H), 3.38-3.28 (m, 1H), 3.13 (dd, J=13.1,7.9Hz, 1H), 2.80 (dd, J=13.2,6.3Hz, 1H), 1.65-1.60 (m, 1H), 1.59-1.51 (m, 2H), 1.50-1.42 (m, 1H), 1.45-1.35 (m, 1H), 1.30-1.27 (m, 12H), 0.92-0.75 (m, 1H); 13cNMR (100MHz, CDCl 3) δ 207.3,149.1,137.0,128.9,125.1,51.8,50.3,43.8,43.6,34.3,31.3,26.4,25.2,24.2,21.7; IR (film) 2962,2933,2858,1487,1444,1282,1254,874,833,802cm -1; HRMS (EI) CalcdforC 19h 29nS303.2021, Found303.2023.
Embodiment 12
The synthesis of compound 2l:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), N-formyl radical-2-phenyl-ethyl amine (1.5mmol; 223.5mg), by α-methyl-p-tert.-butyl phenylpropionaldehyde (0.3mmol, 61.3mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 24 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow liquid 2l (63.0mg through column chromatography for separation, 62%), R f=0.50 (PE:EA=10:1). 1hNMR (400MHz, CDCl 3) δ 7.33-7.27 (m, 3H), 7.26-7.19 (m, 2H), 7.11 (d, J=8.2Hz, 2H), 7.01 (d, J=6.9Hz, 2H), 6.82 (br, 1H), 4.01-3.87 (m, 1H), 3.70-3.62 (m, 1H), 3.00 (dd, J=13.2,8.4Hz, 1H), 2.82-2.75 (m, 2H), 2.74-2.64 (m, 1H), 2.62-2.52 (m, 1H), 1.30 (s, 9H), (1.27 d, J=6.6Hz, 3H); 13cNMR (100MHz, CDCl 3) δ 209.2,149.3,138.2,136.6,128.7,128.7,128.6,126.7,125.2,52.8,46.2,42.9,34.4,33.7,31.4,20.7; IR (film) 3283,2963,2868,1519,1454,1268,1108,981,700cm -1; HRMS (EI) CalcdforC 22h 29nS339.2021, Found339.2024.
Embodiment 13
The synthesis of compound 2m:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by melonal (0.3mmol; 42.1mg), N-formyl morpholine (1.5mmol, 172.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 20 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain colourless oil liquid 2m (48.2mg through column chromatography for separation, 67%), R f=0.5 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 5.15-4.96 (m, 1H), 4.54-4.29 (m, 2H), 3.84-3.78 (m, 2H), 3.77-3.75 (m, 2H), 3.73-3.67 (m, 2H), 2.98 (dd, J=13.2,6.6Hz, 1H), 2.03-1.86 (m, 3H), 1.66 (s, 3H), 1.57 (s, 3H), 1.56-1.49 (m, 1H), 1.21 (d, J=6.6Hz, 3H); 13cNMR (100MHz, CDCl 3) δ 209.9,132.2,123.8,66.6,66.6,50.2,49.7,40.8,37.4,25.7,25.6,21.2,17.7; IR (film) 2963,2926,2856,1468,1432,1260,1085,1017,795cm -1; HRMS (EI) CalcdforC 13h 23nOS241.1500, Found241.1501.
Embodiment 14
The synthesis of compound 2n:
Na is added in reaction tubes 2s9H 2o (0.7mmol, 168mg), cholesterol derivative (aldehyde) (0.2mmol, 91.2mg), by N-formyl morpholine (1.0mmol, 115mg), pyridine (1.0mmol, 79mg) water-soluble (0.3mL) and ethylene glycol (0.3mL) add in reaction tubes, then by K 2s 2o 8(0.36mmol, 97.3mg) adds in reaction system, stirs 12 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain pale yellow oily liquid body 2n (60mg through column chromatography for separation, 54%), R f=0.4 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 5.37 – 5.29 (m, 1H), 4.39-4.29 (m, 2H), 3.84-3.69 (m, 6H), 3.52 (t, J=5.9Hz, 2H), 3.17-3.08 (m, 1H), 2.94 (dd, J=8.7, 6.8Hz, 2H), 2.34-2.28 (m, 1H), 2.20-2.10 (m, 1H), 2.03-1.91 (m, 4H), 1.88-1.79 (m, 3H), 1.60-1.29 (m, 12H), 1.16-1.00 (m, 9H), 0.97 (s, 3H), 0.90 (d, J=6.5Hz, 3H), 0.86 (d, J=1.7Hz, 3H), 0.84 (d, J=1.7Hz, 3H), 0.66 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 203.7,140.7,121.6,79.2,66.6,66.5,66.5,56.7,56.1,50.2,50.1,49.9,42.3,40.1,39.8,39.5,39.2,37.2,36.8,36.2,35.7,31.9,31.9,29.8,28.5,28.2,28.0,24.3,23.8,22.8,22.5,21.0,19.3,18.7,11.8, IR (KBr) 3455,2958,1633,1434,1383,1261,1109,1021,804, HRMS (ESI) CalcdforC 35h 59nO 2s [M+H] +558.4345, Found558.4339.
Embodiment 15
The synthesis of compound 3a:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl radical propylamine (1.5mmol, 130.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 10 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow liquid 3a (34.5mg through column chromatography for separation, 64%), R f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.72 (d, J=7.3Hz, 2H), 7.60 (br, 1H), 7.45 (t, J=7.3Hz, 1H), 7.37 (t, J=7.5Hz, 2H), 3.78 (dd, J=13.6,6.4Hz, 2H), 1.96-1.68 (m, 2H), 1.04 (t, J=7.4Hz, 3H); 13cNMR (100MHz, CDCl 3) δ 199.2,142.0,130.9,128.4,126.5,48.4,21.4,11.5; IR (film) 3259,2963,2931,2873,1523,1486,1449,1390,1347,1261,1223,1064,1013,946,767,693cm -1; MS (EI) m/z (%) 179 (60), 121 (100), 77 (65).
Embodiment 16
The synthesis of compound 3b:
Na is added in reaction tubes 2s9H 2o (1.75mmol; 420mg); N-formyl radical-2-phenyl-ethyl amine (2.5mmol, 372.5mg), by phenyl aldehyde (0.5mmol; 53mg) water-soluble (1mL) adds in reaction tubes; again BPO (1.25mmol, 302.5mg) is added in reaction system, stir 10 hours at 100 DEG C; after TLC detection reaction; drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction; anhydrous sodium sulfate drying; filter, concentrated, obtain yellow solid 3b (98.9mg through column chromatography for separation; 82%), R f=0.40 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.56-7.54 (m, 2H), 7.47 (br, 1H), 7.37-7.33 (m, 1H), 7.28-7.25 (m, 4H), 7.20-7.18 (m, 3H), 4.02 (q, J=6.3Hz, 2H), (3.01 t, J=6.9Hz, 2H); 13cNMR (100MHz, CDCl 3) δ 199.2,141.9,138.2,131.0,128.9,128.7,128.5,126.9,126.5,47.4,33.8; IR (film) 3032,2963,1531,1488,1452,1261,1095,1027,802,695cm -1; MS (EI) m/z (%) 241 (25), 121 (40), 104 (100).
Embodiment 17
The synthesis of compound 3c:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), N-formyl radical benzylamine (1.5mmol; 202.5mg), by phenyl aldehyde (0.3mmol, 31.8mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 21 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid 3c (38.9mg through column chromatography for separation, 57%), R f=0.30 (PE:EA=5:1). 1hNMR (400MHz, CDCl 3) δ 7.80-7.67 (m, 3H), 7.51-7.43 (m, 1H), 7.43-7.34 (m, 7H), 5.00 (d, J=5.1Hz, 2H); 13cNMR (100MHz, CDCl 3) δ 199.1,141.6,136.2,131.1,129.0,128.5,128.4,128.2,126.7,51.1; IR (film) 2963,2925,1521,1451,1380,1262,1097,1026,802,696cm -1; MS (EI) m/z (%) 227 (60), 121 (50), 91 (90).
Embodiment 18
The synthesis of compound 3d:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl radical Pyrrolidine (1.5mmol, 148.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 8 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain orange oily liquids 3d (49.3mg through column chromatography for separation, 86%), R f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.47-7.28 (m, 5H), 3.96 (t, J=7.1Hz, 2H), 3.45 (t, J=6.8Hz, 2H), 2.14-2.00 (m, 2H), 1.99-1.92 (m, 2H); 13cNMR (100MHz, CDCl 3) δ 197.2,143.9,128.6,128.2,125.5,53.7,53.3,26.4,24.6; IR (film) 2963,2875,1495,1449,1327,1263,1078,1034,800,762,698cm -1; MS (EI) m/z (%) 191 (80), 121 (80), 77 (65).
Embodiment 19
The synthesis of compound 3e:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl piperidine (1.5mmol, 169.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 4 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow oily liquid 3e (40.1mg through column chromatography for separation, 65%), R f=0.60 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.33-7.19 (m, 5H), 4.30 (t, J=5.2Hz, 2H), 3.46 (t, J=5.6Hz2H), 1.77 (dt, J=11.1,5.5Hz, 2H), 1.70 (dt, J=11.3,5.4Hz, 2H), 1.52 (dt, J=11.5,5.7Hz, 2H); 13cNMR (100MHz, CDCl 3) δ 199.5,143.3,128.3,128.3,125.3,53.1,50.5,26.8,25.4,24.1; IR (film) 2939,2857,1494,1478,1444,1294,1261,1244,1136,1013,801,759,698cm -1; MS (EI) m/z (%) 205 (80), 204 (100), 121 (95).
Embodiment 20
The synthesis of compound 3f:
Na is added in reaction tubes 2s9H 2o (1.75mmol; 420mg); by phenyl aldehyde (0.5mmol, 53mg), N-formyl morpholine (2.5mmol; 287.5mg) water-soluble (1mL) adds in reaction tubes; again BPO (1.25mmol, 302.5mg) is added in reaction system, stir 12 hours at 100 DEG C; after TLC detection reaction; drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction; anhydrous sodium sulfate drying; filter, concentrated, obtain yellow liquid 3f (77.4mg through column chromatography for separation; 75%), R f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.29-7.20 (m, 5H), 4.53-4.24 (m, 2H), 3.95-3.72 (m, 2H), 3.56-3.54 (m, 4H); 13cNMR (100MHz, CDCl 3) δ 201.0,142.5,128.8,128.5,125.8,66.7,66.5,52.5,49.5; IR (film) 2962,2923,2853,1495,1479,1434,1291,1260,1228,1112,1026,873,803,760,696cm -1; MS (EI) m/z (%) 207 (65), 121 (100).
Embodiment 21
The synthesis of compound 3g:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl radical sulfo-morpholine (1.5mmol, 196.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 8 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow liquid 3g (44.8mg through column chromatography for separation, 67%), R f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.34-7.22 (m, 3H), 7.20-7.12 (m, 2H), 4.78-4.48 (m, 2H), 3.78-3.75 (m, 2H), 2.93-2.72 (m, 2H), 2.65-2.37 (m, 2H); 13cNMR (100MHz, CDCl 3) δ 201.3,142.8,128.6,128.5,125.3,54.4,51.8,28.4,27.2; IR (film) 3053,2961,2910,1470,1433,1361,1296,1236,1189,1037,950,800,758,698cm -1; HRMS (EI) CalcdforC 11h 13nS 2223.0489, Found223.0487.
Embodiment 22
Compound 3h synthesizes:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by phenyl aldehyde (0.5mmol, 53mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, then by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow liquid 3h (71.3mg, 86%) is obtained, R through column chromatography for separation f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.37-7.28 (m, 5H), 3.60 (s, 3H), 3.16 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 200.0,142.6,127.8,127.5,125.0,43.5,42.5; IR (film) 3055,2932,1514,1485,1442,1390,1292,1139,760,698cm -1; MS (EI) m/z (%) 165 (65), 164 (85), 121 (100), 77 (70).
Embodiment 23
The synthesis of compound 3i:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl radical-2-monoethanolamine (1.5mmol, 133.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 5 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain faint yellow solid 3i (40.2mg through column chromatography for separation, 74%), R f=0.30 (PE:EA=2:1). 1hNMR (400MHz, CDCl 3) δ 8.08 (br, 1H), 7.78-7.75 (m, 2H), 7.48-7.45 (m, 1H), 7.40-7.37 (m, 2H), 4.02-4.00 (m, 2H), 3.97-3.96 (m, 2H), 2.12 (br, 1H); 13cNMR (100MHz, CDCl 3) δ 199.9,141.7,131.2,128.5,126.7,60.6,48.5; IR (film) 3367,3263,2963,1528,1450,1262,1098,1026,802,696cm -1; MS (EI) m/z (%) 181 (70), 121 (100).
Embodiment 24
The synthesis of compound 3j:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by phenyl aldehyde (0.3mmol; 31.8mg), N-formyl radical allyl amine (1.5mmol, 127.5mg); pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain weak yellow liquid 3j (42.0mg through column chromatography for separation, 79%), R f=0.50 (PE:EA=5:1). 1hNMR (400MHz, CDCl 3) δ 7.73 (d, J=7.8Hz, 2H), 7.65 (br, 1H), 7.45 (t, J=7.3Hz, 1H), 7.37 (t, J=7.7Hz, 2H), 6.09-5.92 (m, 1H), 5.31 (dd, J=22.0,13.7Hz, 2H), 4.45 (td, J=5.9,1.1Hz, 2H); 13cNMR (100MHz, CDCl 3) δ 199.3,141.7,131.8,131.1,128.5,126.6,118.7,49.0; IR (film) 3260,3080,3028,2963,2911,1517,1486,1448,1374,1261,1218,1066,1029,933,800,769,692cm -1; MS (EI) m/z (%) 177 (20), 162 (100), 121 (60), 77 (60);
Embodiment 25
The synthesis of compound 3k:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 2-tolyl aldehyde (0.5mmol, 60mg),-N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3k (69.0mg is obtained through column chromatography for separation, 77%), R f=0.50 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.33-7.27 (m, 1H), 7.18 (d, J=5.9Hz, 2H), 7.12 (d, J=7.6Hz, 1H), 3.64 (s, 3H), 3.21 (s, 3H), 2.40 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 201.4,143.3138.0,129.2,128.1,126.2,122.5,44.0,43.0,21.2, IR (film) 3033,2929,1513,1453,1390,1296,1139,1024,787,702cm -1, MS (EI) m/z (%) 179 (70), 178 (85), 135 (100), 91 (65).
Embodiment 26
The synthesis of compound 3l:
Na is added in reaction tubes 2s9H 2o (3.5mmol, 840mg), by 3-tolyl aldehyde (0.5mmol, 60mg), N, N--dimethyl formamide (5mmol, 365mg) water-soluble (1mL) adds in reaction tubes, then by BPO (2.5mmol, 605mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3l (71.6mg, 80%) is obtained, R through column chromatography for separation f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.35-7.25 (m, 1H), 7.18 (d, J=6.0Hz, 2H), 7.12 (d, J=7.5Hz, 1H), 3.64 (s, 3H), 3.21 (s, 3H), 2.40 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 201.2,143.2,138.0,129.1,128.0,126.1,122.4,44.0,43.0,21.2; IR (film) 3031,2961,2931,1583,1453,1389,1296,1260,1138,1022,786,702cm -1; MS (EI) m/z (%) 179 (80), 178 (90), 135 (100), 91 (55).
Embodiment 27
The synthesis of compound 3m:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 4-tolyl aldehyde (0.5mmol, 60mg), N, N--dimethyl formamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3m (58.2mg is obtained through column chromatography for separation, 65%), R f=0.50 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.19 (d, J=8.0Hz, 2H), 7.13 (d, J=8.3Hz, 2H), 3.57 (d, J=0.9Hz, 3H), 3.16 (d, J=0.8Hz, 3H), 2.33 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 201.4,140.4,138.6,128.8,125.8,44.1,43.2,21.1, IR (film) 3024,2924,2870,1517,1502,1453,1388,1291,1137,996,884,814cm -1, MS (EI) m/z (%) 179 (75), 178 (100), 135 (98), 91 (65).
Embodiment 28
The synthesis of compound 3n:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 3-fluorobenzaldehyde (0.5mmol, 62mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 3 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3n (59.5mg is obtained through column chromatography for separation, 65%), R f=0.60 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.34-7.28 (m, 1H), 7.08-6.99 (m, 3H), 3.57 (s, 3H), 3.15 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 199.2 (s), 162.2 (d, J=247.8Hz), 145.0 (d, J=7.4Hz), 130.1 (d, J=8.5Hz), 121.3 (d, J=3.0Hz), 115.4 (d, J=21.0Hz), 113.1 (d, J=23.1Hz), 44.0,43.1, 19fNMR (377MHz, CDCl 3) δ-112.10, IR (film) 3054,2931,1583,1515,1481,1428,1391,1294,1137,826,786,695cm -1, MS (EI) m/z (%) 183 (70), 182 (80), 139 (100), 95 (50).
Embodiment 29
The synthesis of compound 3o:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 3-chlorobenzaldehyde (0.5mmol, 70.3mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, pale yellow oily liquid body 3o (51.9mg is obtained through column chromatography for separation, 52%), R f=0.50 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.28-7.22 (m, 3H), 7.14-7.12 (m, 1H), 3.54 (s, 3H), 3.13 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 199.1,144.7,134.2,129.6,128.5,125.8,123.7,44.0,43.1, IR (film) 3053,2961,2934,1591,1564,1514,1470,1389,1286,1141,1078,1014,786,751,694cm -1, HRMS (EI) CalcdforC 9h 10clNS199.0222, Found199.0221.
Embodiment 30
The synthesis of compound 3p:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 3-bromobenzaldehyde (0.5mmol, 92.5mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3p (69.2mg is obtained through column chromatography for separation, 57%), R f=0.50 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.46-7.43 (m, 2H), 7.22-7.21 (m, 2H), 3.57 (s, 3H), 3.16 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 199.0,144.9,131.5,129.9,128.6,124.2,122.3,44.1,43.1, IR (film) 3051,2931,1559,1514,1468,1390,1285,1141,1072,1010,894,785,728,693cm -1, HRMS (EI) CalcdforC 9h 10brNS242.9717, Found242.9715.
Embodiment 31
The synthesis of compound 3q:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 4-methoxybenzaldehyde (0.5mmol, 68mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3q (75.0mg is obtained through column chromatography for separation, 77%), R f=0.40 (PE:EA=5:1), 1hNMR (400MHz, CDCl 3) δ 7.29 (d, J=8.7Hz, 2H), 6.85 (d, J=8.7Hz, 2H), 3.81 (s, 3H), 3.58 (s, 3H), 3.21 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 201.3,160.0,135.8,127.9,113.5,55.4,44.3,43.5, IR (film) 2962,2928,2857,1505,1457,1391,1261,1097,1031,801cm -1, MS (EI) m/z (%) 195 (85), 151 (100), 107 (65).
Embodiment 32
The synthesis of compound 3r:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), 3, 4, 5-TMB (0.5mmol, 98.1mg), by N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow solid 3r (117.0mg is obtained through column chromatography for separation, 92%), R f=0.40 (PE:EA=3:1), 1hNMR (400MHz, CDCl 3) δ 6.51 (s, 2H), 3.84 (s, 6H), 3.83 (s, 3H), 3.58 (s, 3H), 3.19 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 201.0,153.1,138.8,138.1,103.1,60.8,56.2,44.2,43.2, IR (film) 2962,2937,2835,1581,1502,1453,1409,1334,1260,1235,1123,1006,915,799,730cm -1, MS (EI) m/z (%) 255 (100), 211 (25).
Embodiment 33
The synthesis of compound 3s:
Na is added in reaction tubes 2s9H 2o (3.5mmol, 840mg), by 3-trifluoromethylated benzaldehyde (0.5mmol, 87mg), N, dinethylformamide (5mmol, 365mg) water-soluble (1mL) adds in reaction tubes, then by BPO (2.5mmol, 605mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3s (73.1mg, 63%) is obtained, R through column chromatography for separation f=0.40 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.56-7.47 (m, 4H), 3.59 (s, 3H), 3.15 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 199.0,143.8,130.70 (q, J=32.6Hz), 129.0,128.9,125.1 (q, J=3.7Hz), 123.5 (q, J=271Hz), 122.6 (q, J=3.9Hz), 44.1,43.1; 19fNMR (376MHz, CDCl 3) δ-62.75; IR (film) 2937,1518,1393,1334,1263,1125,1072,1015,908,803,700cm -1; MS (EI) m/z (%) 233 (70), 232 (100), 189 (75), 145 (30).
Embodiment 34
The synthesis of compound 3t:
Na is added in reaction tubes 2s9H 2o (3.5mmol, 840mg), by 4-trifluoromethylated benzaldehyde (0.5mmol, 87mg), N, dinethylformamide (5mmol, 365mg) water-soluble (1mL) adds in reaction tubes, then by BPO (2.5mmol, 605mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3t (84.2mg, 72%) is obtained, R through column chromatography for separation f=0.40 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.61 (d, J=8.2Hz, 2H), 7.40 (d, J=8.1Hz, 2H), 3.60 (s, 3H), 3.15 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 199.2,146.5,130.4 (q, J=32.8Hz), 126.0,125.5 (q, J=3.7Hz), 123.7 (q, J=270.5Hz), 44.0,43.0; 19fNMR (376MHz, CDCl 3) δ-62.83; IR (film) 2962,2934,1525,1504,1395,1324,1294,1260,1106,1066,1020,837,796,691cm -1; MS (EI) m/z (%) 233 (70), 232 (100), 189 (70), 145 (40).
Embodiment 35
The synthesis of compound 3u:
Na is added in reaction tubes 2s9H 2o (3.5mmol, 840mg), 4-chlorobenzaldehyde (0.5mmol, 70.2mg), by N, dinethylformamide (5mmol, 365mg) water-soluble (1mL) adds in reaction tubes, then by BPO (2.5mmol, 605mg) add in reaction system, stir 12 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3u (88.5mg, 89%) is obtained, R through column chromatography for separation f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.31 (d, J=8.6Hz, 2H), 7.24 (d, J=8.6Hz, 2H), 3.57 (s, 3H), 3.15 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 199.3,141.4,134.1,128.2,127.0,43.9,43.0; IR (film) 2962,2931,1591,1513,1486,1392,1288,1261,1140,1090,996,823,729cm -1; MS (EI) m/z (%) 199 (70), 198 (100), 155 (85).
Embodiment 36
The synthesis of compound 3v:
Na is added in reaction tubes 2s9H 2o (3.5mmol, 840mg), 4-bromobenzaldehyde (0.5mmol, 92.6mg), by N, dinethylformamide (5mmol, 365mg) water-soluble (1mL) adds in reaction tubes, then by BPO (2.5mmol, 605mg) add in reaction system, stir 12 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow solid 3v (116.0mg, 95%) is obtained, R through column chromatography for separation f=0.50 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.45 (d, J=8.3Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 3.54 (s, 3H), 3.13 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 199.5,141.9,131.3,127.3,122.5,44.0,43.1; IR (film) 3024,2961,2932,1584,1514,1482,1391,1287,1140,1070,993,820,711cm -1; MS (EI) m/z (%) 245 (60), 244 (100), 243 (60), 242 (100), 201 (55), 199 (55), 120 (80).
Embodiment 37
The synthesis of compound 3w:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), 2-naphthaldehyde (0.5mmol, 78mg), by N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, then by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3w (98.6mg, 92%) is obtained, R through column chromatography for separation f=0.40 (PE:EA=5:1); 1hNMR (400MHz, CDCl 3) δ 7.84-7.82 (m, 3H), 7.77 (d, J=1.2Hz, 1H), 7.54-7.47 (m, 2H), 7.43 (dd, J=8.5,1.7Hz, 1H), 3.65 (s, 3H), 3.21 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 201.2,140.5,133.0,132.7,128.3,128.1,127.7,126.7,126.7,124.7,123.9,44.2,43.2; IR (film) 2962,1515,1392,1259,1087,1013,793,689cm -1; MS (EI) m/z (%) 215 (100), 171 (85), 127 (65).
Embodiment 38
The synthesis of compound 3x:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 2 thiophene carboxaldehyde (0.5mmol, 56mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3x (81.0mg is obtained through column chromatography for separation, 95%), R f=0.60 (PE:EA=10:1), 1hNMR (400MHz, CDCl 3) δ 7.37 (d, J=5.1Hz, 1H), 7.09 (d, J=3.6Hz, 1H), 6.95 (t, J=4.4Hz, 1H), 3.55 (s, 3H), 3.41 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 191.4,145.1,129.2,126.4,126.3,44.5, IR (film) 3071,2962,2928,2869,1503,1453,1386,1354,1262,1124,1048,794,707cm -1, MS (EI) m/z (%) 171 (65), 127 (100).
Embodiment 39
The synthesis of compound 3y:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by 2-pyridylaldehyde (0.5mmol, 53.5mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, pale yellow oily liquid body 3y (43.9mg is obtained through column chromatography for separation, 53%), R f=0.40 (PE:EA=1:1), 1hNMR (400MHz, CDCl 3) δ 8.49 (d, J=4.8Hz, 1H), 7.72 (t, J=7.7Hz, 1H), 7.56 (d, J=7.9Hz, 1H), 7.26-7.19 (m, 1H), 3.59 (s, 3H), 3.17 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 198.0,159.4,148.0,136.9,123.2,123.1,43.7,43.2, IR (film) 3048,2961,2929,1585,1524,1464,1427,1393,1300,1145,1014,785,745,702cm -1, MS (EI) m/z (%) 166 (45), 123 (100), 79 (75),
Embodiment 40
The synthesis of compound 3z:
Na is added in reaction tubes 2s9H 2o (1.75mmol, 420mg), by cumarone-2-formaldehyde (0.5mmol, 73.1mg), N, dinethylformamide (2.5mmol, 182.5mg) water-soluble (0.5mL) adds in reaction tubes, again by BPO (1.25mmol, 302.5mg) add in reaction system, stir 12 hours at 60 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, add ethyl acetate (10mL*3) extraction again, anhydrous sodium sulfate drying, filter, concentrated, yellow oily liquid 3z (71.7mg is obtained through column chromatography for separation, 70%), R f=0.40 (PE:EA=10:1), 1hNMR (400MHz, CDCl 3) δ 7.58 (d, J=7.8Hz, 1H), 7.44 (d, J=8.3Hz, 1H), 7.33 (t, J=7.7Hz, 1H), 7.29 (s, 1H), 7.23 (t, J=7.5Hz, 1H), 3.55 (s, 3H), 3.42 (s, 3H), 13cNMR (100MHz, CDCl 3) δ 186.7,154.2,153.3,127.4,126.3,123.5,122.0,112.1,111.6,44.3,44.1, IR (film) 2962,2931,1567,1507,1447,1390,1295,1258,1127,1005,934,818,751cm -1, HRMS (EI) CalcdforC 11h 11nOS205.0561, Found205.0560.
Embodiment 41
The synthesis of compound 3aa:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), 4-hydroxy benzaldehyde (0.3mmol, 36.6mg), by DMF (1.5mmol, 109.5mg), pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 7 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain faint yellow solid 3aa (33.1mg through column chromatography for separation, 61%), R f=0.40 (PE:EA=1:1); 1hNMR (400MHz, CDCl 3) δ 7.19 (d, J=8.5Hz, 2H), 6.72 (d, J=8.5Hz, 2H), 5.62 (br, 1H), 3.59 (s, 3H), 3.20 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 201.4,156.4,135.6,127.9,115.2,44.4,43.6; IR (film) 3123,2925,2856,1607,1506,1457,1390,1270,1231,1138,883cm -1; MS (EI) m/z (%) 181 (85), 180 (80), 137 (100).
Embodiment 42
The synthesis of compound 3ab:
Na is added in reaction tubes 2s9H 2o (1.05mmol, 252mg), by salicylic aldehyde (0.3mmol, 36.6mg), DMF (1.5mmol, 109.5mg), pyridine (1.5mmol, 118.5mg) water-soluble (0.6mL) adds in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 6 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain pale yellow oily liquid body 3ab (46.2mg through column chromatography for separation, 85%), R f=0.35 (PE:EA=2:1); 1hNMR (400MHz, CDCl 3) δ 7.95 (s, 1H), 7.12 (t, J=7.1Hz, 1H), 6.99 (d, J=7.3Hz, 1H), 6.90-6.74 (m, 2H), 3.48 (s, 3H), 3.13 (s, 4H); 13cNMR (100MHz, CDCl 3) δ 196.1,152.5,152.5,130.4,127.5,127.5,126.3,119.4,117.4,44.1,42.7; IR (KBr) 3412,2963,1602,1528,1448,1396,1294,1142,1106,821,756; HRMS (ESI) CalcdforC 9h 11nOS [M+H] +182.0640, Found182.0648.
Embodiment 43
The synthesis of compound 3ac:
Na is added in reaction tubes 2s9H 2o (1.05mmol; 252mg); 2-formyl radical estrone (0.3mmol; 89.5mg); by N-formyl morpholine (1.5mmol, 172.5mg), pyridine (1.5mmol; 118.5mg) water-soluble (0.3mL) and ethylene glycol (0.3mL) add in reaction tubes, then by K 2s 2o 8(0.54mmol, 146.0mg) adds in reaction system, stirs 10 hours at 100 DEG C, after TLC detection reaction, drop to room temperature, in system, add water 10mL dilute, then add ethyl acetate (10mL*3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid 3ac (84.5mg through column chromatography for separation, 71%), R f=0.4 (PE:EA=3:1); 1hNMR (400MHz, CDCl 3) δ 7.78 (br, 1H), 6.88 (s, 1H), 6.69 (s, 1H), 4.17-3.90 (m, 2H), 3.85-3.65 (m, 4H), 2.83 (d, J=4.6Hz, 2H), 2.49 (dd, J=18.9,8.6Hz, 1H), 2.36-1.85 (m, 7H), 1.67-1.29 (m, 7H), 0.89 (s, 3H); 13cNMR (100MHz, CDCl 3) δ 220.8,197.0,151.5,140.2,131.4,124.5,123.1,117.9,66.6,50.3,47.8,43.6,38.1,35.7,31.4,29.2,26.2,25.8,21.5,13.8; IR (KBr) 3434,2962,2927,2857,1735,1616,1436,1261,1130,1029,803; HRMS (ESI) CalcdforC 23h 29nO 3s [M+H] +400.1946, Found400.1931.

Claims (14)

1. a synthetic method for thioamide analog compound, is characterized in that, with aldehyde and formyl radical aliphatic amide for reaction raw materials, with Na 2s9H 2o is sulfiding reagent, and under oxygenant effect, under 25 ~ 100 DEG C of conditions, in reaction solvent, reaction obtains such as formula the thioamide analog compound shown in (II) for 3 ~ 24 hours; Described reaction process is as shown in reaction formula;
Wherein, R is alkyl, aryl; R 1/ R 2alkyl, containing arylalkyl or hydrogen.
2. the synthetic method of thioamide analog compound as claimed in claim 1, it is characterized in that, in described reaction formula (a), R is isobutyl-, 2-phenylethyl, benzyl, cyclohexyl, 2, 6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1, 5 dimethyl-4-thiazolinyl hexyls, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-p-methoxy-phenyl, 3, 4, 5-trimethoxyphenyl, 3-trifluoromethyl, 4-trifluoromethyl, 4-chloro-phenyl-, 4-bromophenyl, 4-hydroxy phenyl, 2-hydroxy phenyl, 2-naphthyl, 2-thiophene, 2-pyridine, 2-cumarone, cholesterol derivative or estrone derivative, R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen, propyl group/hydrogen, benzyl/hydrogen, allyl group/hydrogen,
3. the synthetic method of thioamide analog compound as claimed in claim 1, it is characterized in that, described reaction solvent is N, dinethylformamide, methyl-sulphoxide, N, the mixing solutions of N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, Nitromethane 99Min., ethylene glycol, acetonitrile, Isosorbide-5-Nitrae-dioxane, p-Xylol, water or its arbitrary combination.
4. the synthetic method of thioamide analog compound as claimed in claim 1, is characterized in that, described aldehyde and described sulfiding reagent Na 2s9H 2the consumption mol ratio of O is 1:1 ~ 7.
5. the synthetic method of thioamide analog compound as claimed in claim 1, it is characterized in that, the consumption mol ratio of described aldehyde and described formyl radical aliphatic amide is 1:1 ~ 10.
6. the synthetic method of thioamide analog compound as claimed in claim 1, it is characterized in that, described oxygenant is 1,4-benzoquinones, dibenzoyl peroxide, Potassium Persulphate, oxygen, metachloroperbenzoic acid, iodobenzene diacetate, iron nitrate or peroxide list potassium sulfonate, the consumption mol ratio of described aldehyde and described oxygenant is 1:1 ~ 5.
7. the synthetic method of thioamide analog compound as claimed in claim 1, it is characterized in that, additive can also be comprised in described synthesis, described additive is pyridine, triethylamine, tetrabutylammonium chloride, Tetrabutyl amonium bromide or tetrabutylammonium iodide, and the molar weight of described additive mostly is 5 times of described aldehyde most.
8. the synthetic method of thioamide analog compound as claimed in claim 7; it is characterized in that; when substrate aldehyde and formyl radical aliphatic amide are liquid; said method comprising the steps of: first in reaction vessel, add sulfiding reagent; then adding in reaction vessel by being dissolved in the substrate aldehyde of solvent, formyl radical aliphatic amide and additive, finally adding oxygenant and reacting.
9. the synthetic method of thioamide analog compound as claimed in claim 7; it is characterized in that; when aldehyde be liquid, formyl radical aliphatic amide be solid time; said method comprising the steps of: the formyl radical aliphatic amide first adding sulfiding reagent and solid in reaction vessel; then the substrate aldehyde and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant and react.
10. the synthetic method of thioamide analog compound as claimed in claim 7; it is characterized in that; when aldehyde be solid, formyl radical aliphatic amide be liquid time; said method comprising the steps of: the aldehyde first adding sulfiding reagent, solid in reaction vessel; then the formyl radical aliphatic amide and additive that are dissolved in solvent are added in reaction vessel, finally add oxygenant and react.
The synthetic method of 11. thioamide analog compounds as claimed in claim 7; it is characterized in that; when aldehyde and formyl radical aliphatic amide are solid; said method comprising the steps of: first in reaction vessel, add sulfiding reagent, aldehyde and formyl radical aliphatic amide; then the additive being dissolved in solvent is added in reaction vessel, finally add oxygenant and react.
The thioamide analog compound that 12. synthetic methods as claimed in claim 1 prepare, is characterized in that, its structure such as formula shown in (II),
Wherein, R is isobutyl-, 2-phenylethyl, benzyl, cyclohexyl, 2, 6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1, 5 dimethyl-4-thiazolinyl hexyls, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-p-methoxy-phenyl, 3, 4, 5-trimethoxyphenyl, 3-trifluoromethyl, 4-trifluoromethyl, 4-chloro-phenyl-, 4-bromophenyl, 4-hydroxy phenyl, 2-hydroxy phenyl, 2-naphthyl, 2-thiophene, 2-pyridine, 2-cumarone, cholesterol derivative or estrone derivative, R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen, propyl group/hydrogen, benzyl/hydrogen, allyl group/hydrogen,
13. 1 kinds of thioamide analog compounds, is characterized in that, its structure is such as formula shown in (II):
Wherein, R is isobutyl-, cyclohexyl, 2,6-dimethyl-5-thiazolinyl heptyl, 1-methyl-2-(4-tert-butyl-phenyl) ethyl, 1,5 dimethyl-4-thiazolinyl hexyls, phenyl, 3-chloro-phenyl-, 3-bromophenyl, 2-cumarone, cholesterol derivative or estrone derivative; R 1/ R 2methyl/methyl, 2-phenylethyl/hydrogen, 2-hydroxyethyl/hydrogen,
14. thioamide analog compounds as claimed in claim 13, it is characterized in that, described thioamide analog compound comprises:
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CN110981850B (en) * 2019-12-13 2020-11-13 华南农业大学 Green preparation method of thioamide
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