CN117820175A - Synthesis method of o-amino aryl sulfoxide compound - Google Patents

Synthesis method of o-amino aryl sulfoxide compound Download PDF

Info

Publication number
CN117820175A
CN117820175A CN202311827694.1A CN202311827694A CN117820175A CN 117820175 A CN117820175 A CN 117820175A CN 202311827694 A CN202311827694 A CN 202311827694A CN 117820175 A CN117820175 A CN 117820175A
Authority
CN
China
Prior art keywords
compound
reaction
sulfoxide compound
synthesizing
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311827694.1A
Other languages
Chinese (zh)
Inventor
高洪银
郭召全
杨琳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong University
Original Assignee
Shandong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong University filed Critical Shandong University
Priority to CN202311827694.1A priority Critical patent/CN117820175A/en
Publication of CN117820175A publication Critical patent/CN117820175A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
    • C07B45/04—Formation or introduction of functional groups containing sulfur of sulfonyl or sulfinyl groups
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—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
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a synthesis method of an o-amino aryl sulfoxide compound, which realizes the efficient and high-region-selective synthesis of the o-amino aryl sulfoxide through the [2,3] -sigma-rearrangement reaction participated by aryl hydroxylamine compound and aryl/alkyl thiophthalimide under the condition of no transition metal catalysis. The substrate of the invention has wide range and good compatibility of functional groups, successfully realizes the ortho-sulfoxide modification of the aromatic amine of the fluorine-containing compound, and has important significance for further development and application in the fields of functional materials, life, medical science and the like.

Description

Synthesis method of o-amino aryl sulfoxide compound
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to a synthesis method of an o-amino aryl sulfoxide compound.
Background
Sulfoxide structures are widely used synthetic intermediates in organic chemistry and are also very valuable backbones because of their unique structure, with wide application in many chiral ligands, bioactive drugs and functional materials. Sulfoxides have unique sulfinyl functions, have various biological activities, are of great significance to industrial production of medicines and pesticides, and particularly aryl sulfoxide compounds have various pharmacological properties and are used for treating various diseases due to the unique anti-inflammatory and antibacterial activities. In addition, sulfoxides are also widely used as multifunctional directing groups or key intermediates for various organic transformations, such as directed C-H functionalization reactions, pummers reactions and related rearrangement reactions.
The synthesis of sulfoxides is currently very diverse and the common strategy is to use oxidizing or peroxidating agents to oxidize the thioether directly to the sulfoxide. However, the synthetic method has complex process, poor stability, extremely easy excessive oxidation to sulfone compounds, and environmental friendliness, and needs to consider the type of oxidant and oxidation conditions during use. The most common oxidizing agent is hydrogen peroxide, for example: ce (OTf) is used in CN107722042A 4 /H 2 O 2 The oxidation system selectively oxidizes the S atom to sulfoxide. However, high concentrations of hydrogen peroxide are explosive and dangerous to use.
The oxidation of thioethers to sulfoxides can also be accomplished using strong acids such as nitric acid, but such methods are not controllable and the range of substrates is relatively limited. Ammonium cerium nitrate, which is currently prepared using nitric acid, is a commonly used nitrate-based thioether oxidant, but is only applicable to diaryl sulfides.
The sulfoxide unit can be effectively constructed by utilizing transition metal catalysis. A precursor compound capable of generating a sulfinate anion intermediate is firstly constructed, and then the sulfinate anion can be cross-coupled with various halides, triflate, iodonium salt or boron under the catalysis of palladium to form a sulfoxide compound. Although the strategy widens the range of sulfoxide compounds, the method has the defects of expensive catalyst, difficult synthesis and the like.
The report of synthesizing sulfoxide by using visible light catalysis is less, mainly due to the lack of a sulfoxide synthesis photoinductors. More recently Wu and Kuang have recorded the radical pathway from sulfinic acid and four substituted Hantzsch esters to sulfoxides in the presence of an N-heterocyclic carbene and a photocatalyst.
The sulfoxide moiety can also be prepared from organometallic reagents and DABSO in the presence of trimethylsilyl chloride.
Despite some advances in the above-described methods, there remains a great need for more efficient, environmentally friendly and simple-to-operate schemes for synthesizing structurally diverse sulfoxide compounds from readily available materials.
In addition, aryl hydroxylamine is also a kind of organic molecules and prodrugs with wide application, and is widely applied to the fields of organic synthesis, biological medicine and the like. Aryl hydroxylamine molecules contain a relatively low bond energy nitrogen-oxygen bond (about 53kcal mol -1 ) The low bond energy of the nitrogen-oxygen bond is caused by the mutual repulsive interaction of the lone pair electron pair on the nitrogen atom and the oxygen atom, the weaker nitrogen-oxygen bond is easy to break in the reaction process, and a new bond with stronger bond energy is easy to form, so that the compound is easy to undergo rearrangement reaction. Therefore, rearrangement of hydroxylamine and its derivatives is a common method for preparing different heterocyclic compounds, biaryl compounds and functionalized aromatic amines.
Therefore, based on the research of rearrangement reaction of aryl hydroxylamine and the requirement of sulfoxide compounds, the development of an environment-friendly o-amino aryl sulfoxide compound with wide application range has great significance.
Disclosure of Invention
In view of the above-mentioned prior art, especially the existing sulfoxide preparation strategies mostly employ oxidizing agents, catalysts, etc., and have the defects of complex reaction, higher preparation cost and narrow application range of substrates, the inventors of the present invention have conducted intensive and extensive research on the synthesis of sulfoxide compounds, so as to obtain an o-amino aryl sulfoxide compound preparation strategy which has no transition metal catalysis, does not employ oxidation strategies, has a wide substrate application range, and is environmentally friendly. The inventor of the present invention has found that under the condition of no transition metal catalysis, the efficient and high-regioselectivity synthesis of o-amino aryl sulfoxide can be realized through the [2,3] -sigma-rearrangement reaction of aryl hydroxylamine compound and aryl/alkyl thiophthalimide. The present invention has been achieved based on the above findings.
It is therefore an object of the present invention to provide a method for synthesizing an ortho-amino aryl sulfoxide compound. Compared with the existing preparation strategy adopting an oxidant and a transition metal catalyst, the preparation method disclosed by the invention has the advantages that the aryl/alkyl N-thiophthalimide which is low in cost and easy to prepare is utilized to react with the aryl hydroxylamine compound, the high-efficiency synthesis of the o-amino aryl sulfoxide is realized under the conditions of no transition metal catalysis and no oxidant, and the reaction is environment-friendly.
The technical scheme for achieving the aim of the invention can be summarized as follows:
a synthesis method of an o-amino aryl sulfoxide compound, which has a structure shown in a formula (III):
in the formula (III), ar is a substituted or unsubstituted aryl, heteroaryl or biaryl, R 1 Is one of benzoyl, acetyl, pivaloyl, ester, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl; r is R 2 Is one of a substituted or unsubstituted aryl, heteroaryl or alkyl group;
the method comprises the following steps:
adding the compound (I) and the compound (II) into a solvent in an air atmosphere, adding alkali into the mixed solution for reaction, and purifying after the reaction is finished to obtain an o-amino aryl sulfoxide compound (III);
according to the invention, ar is preferablyR 3 Is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester group, alkoxy, aryl, heteroaryl, oxytrifluoromethyl and silicon group.
According to the invention, preferably R 2 Is thatOne of cyclohexyl, phenethyl and decyl, wherein R 4 Is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro and heteroaryl.
According to the present invention, preferably, the o-aminoaryl sulfoxide compound has the following structure:
according to the present invention, the progress of the reaction can be followed by TLC during the reaction.
According to the invention, the purification method is preferably as follows:
after the reaction is finished, the reaction mixture is concentrated, the crude product is purified and separated by column chromatography, and the eluent of the column chromatography is petroleum ether: ethyl acetate=5:1 to obtain the target compound (III).
According to the present invention, it is preferable that the molar ratio of the compound (I) to the compound (II) is 1: (1-2), further preferably 1: (1.1-1.5); most preferably, the molar ratio of compound (I) to compound (II) is 1:1.2.
According to the invention, preferably, the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium tert-butoxide, sodium tert-butoxide or DBU; most preferably, the base is potassium tert-butoxide.
According to the invention, it is preferred that the molar ratio of compound (I) to base is 0.5: (1-3), further preferably 0.5: (1.1-1.5); most preferably, the molar ratio of compound (I) to base is 1:1.
According to the invention, the solvent is preferably DME (ethylene glycol dimethyl ether), meCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), CHCl 3 Trichloromethane, tolene (toluene), et 2 O (diethyl ether) or THF (tetrahydrofuran); most preferably, the solvent A is DME.
According to the invention, the reaction temperature is preferably-78℃to 25℃and more preferably-70℃to-20℃and most preferably-60 ℃.
According to the invention, said compound (I) has the following structure:
the compounds (I) can be prepared according to the prior art route, the preparation route is as follows:
the synthesis steps are as follows: nitro compound (1.0 eq) and 5% rh/C (0.30 mol% rh) were inert gas-shielded (e.g. nitrogen), dissolved with THF (0.5M), then the reaction system was cooled to 0 ℃, and hydrazine hydrate (1.2 eq) was slowly added dropwise; the reaction mixture is stirred for 1 hour at 0 ℃, then slowly warmed to room temperature and stirred for 2 hours at room temperature, the reaction progress can be detected by TLC, after the reaction is finished, the reaction mixture is filtered through kieselguhr, concentrated by rotary evaporation and recrystallized, and the obtained crude hydroxylamine is directly used in the next step;
adding diethyl ether (0.5M) solution into the crude hydroxylamine, and adding saturated NaHCO 3 The aqueous solution was then cooled to 0deg.C, the corresponding acid chloride (1.1 eq.) was added to the solution, and after the addition was completed, the reaction was stirred at 0deg.C for 5 minutes, and then saturated NH was used 4 The reaction mixture was extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and after removal of the solvent in vacuo, the crude product was subjected to column chromatography (eluent dichloromethane: ethyl acetate=50:1) or recrystallization to give compound (I).
According to the invention, said compound (II) N-thiophthalimide has the following structure:
the compound (II) can be prepared according to the prior art route, and the preparation route is as follows:
method 1:
method 2:
the synthesis steps are as follows:
method 1: sulfonyl chloride (1.0 eq., in CH) was added via a dropping funnel at 0deg.C 2 Cl 2 In 5M) was added dropwise thiophenol/thiol (5 mmol; on CH 2 Cl 2 1M) and Et 3 N (0.01 mL). After stirring for 15 minutes, the mixture was warmed to room temperature and stirred for 30 minutes, then cooled to 0 ℃. The resulting solution was transferred dropwise through a cannula to 0℃phthalimide (1.0 eq.; about 1M in CH) 2 Cl 2 Neutralization) and Et 3 N (1.3 eq) and then the mixture was warmed to room temperature over 1 hour. By H 2 Diluting the solution with CH 2 Cl 2 (3X) extraction followed by Na 2 SO 4 Dried and then concentrated to give the crude product, which is purified using recrystallization. For samples in which large amounts of phthalimide are present, CH is used 2 Cl 2 Dissolving the crude product, diluting with 1M NaOH, and using CH 2 Cl 2 (3X) extraction followed by Na 2 SO 4 Drying, concentrating, and purifying by recrystallization to obtain the N-thiophthalimide compound (II).
Method 2: to a dry, argon flushed round bottom flask equipped with a magnetic stir bar and septum was added N-chlorophthalimide (328 mg,5.0mmol,1.0 eq.), dry MeCN (2.6 mL), and pyridine (2.1 mL). Dried MeCN (2.6 mL) and thiophenol/thiol (5.0 mmol,1.0 eq.) in dried pyridine (2.1 mL) were added dropwise at 0 ℃ over 30 min and the resulting mixture stirred for an additional 30 min. After removing most of the MeCN in vacuo, water (20 mL) was added dropwise over 10 minutes at 0 ℃ and stirred for an additional 10 minutes. The resulting suspension was filtered and the filtrate was washed with ice-cold MeOH (3X 5 mL) to give the corresponding N-thiophthalimide compound (II).
According to the present invention, the by-product phthalimide at the end of the reaction can be recovered by 85 to 95% for the purpose of preparing compound (II) again.
According to the invention, the o-amino aryl sulfoxide compound is widely focused on the aspects of organic synthetic chemistry, material chemistry, pharmaceutical chemistry, chemical biology, particularly pharmaceutical molecular intermediates, natural pharmaceutical modification and the like, and has good application prospect. The compound can stably exist in a neutral buffer solution for a plurality of months, and can stably exist in a phosphate buffer solution with the pH value of 10 for two weeks. They are almost compatible with the functional groups present on most natural products, are an important class of synthetic intermediates in synthetic chemistry, and have great research value and application prospects.
The technical route of the invention is as follows:
the mechanism diagram of [2,3] -sigma-rearrangement reaction related by the invention is as follows:
the invention has the beneficial effects that:
1. the invention reports an o-amino aryl sulfoxide synthesis strategy without transition metal catalysis. The N-thio phthalimide which is cheap and easy to prepare is utilized to react with an aryl hydroxylamine compound, and the high-efficiency synthesis of the o-amino aryl sulfoxide is realized under the condition of no transition metal catalysis. The strategy has wide substrate range and good functional group compatibility, successfully realizes the ortho sulfoxide modification of the aromatic amine of the fluorine-containing compound, and has important significance for the further development and application of the fluorine-containing compound in the fields of functional materials, life, medical science and the like.
2. The present invention is not limited to the synthesis of a single aryl sulfoxide compound. The synthesized o-amino aryl sulfoxide compound has wide variety, and one side of the sulfoxide structure may be unsubstituted or substituted aryl radical, and the other side may be chain alkane, cyclic alkane or aliphatic radical with hetero atom.
3. The invention has simple operation, wide substrate adaptability and no transition metal catalysis. The invention has good universality, various aryl hydroxylamines including natural product molecules can effectively realize the sulfinylation of the ortho-carbon hydrogen bond, and the o-amino aryl sulfoxide compound with excellent regioselectivity and various structures is prepared in good yield.
4. The raw materials of aryl hydroxylamine and N-thiophthalimide of the present invention are easy to prepare. The valence of the sulfur atom in the N-thiophthalimide is positive bivalent, the valence is lower, the electrophilicity is weaker, the prepared raw material can exist stably at normal temperature, the storage is convenient, and the large-scale preparation and transportation are facilitated.
5. The alkali used in the invention is also a common commercial reagent, is very stable, and has the characteristics of low cost, high yield, simple process and less pollution. The invention has simple post-treatment, can be recycled and has wide application prospect.
6. The synthesized o-amino aryl sulfoxide compound has chiral sulfur atoms and has the potential of being split into single chiral compounds. The o-aminoaryl sulfoxide compound contains a nitrogen atom, a sulfur atom and an oxygen atom which are easy to coordinate with metal, so that the asymmetric o-aminoaryl compound can be used as a ligand or a raw material for asymmetric catalytic synthesis.
Drawings
FIG. 1 shows N- (2- (p-toluenesulfonyl) phenyl) benzamide obtained in example 1 1 H-NMR spectrum;
FIG. 2 is a drawing showing N- (2- (p-toluenesulfonyl) phenyl) benzamide obtained in example 1 13 C-NMR spectrum;
FIG. 3 is a schematic diagram of N- (2 '-fluoro-3- (p-toluenesulfonyl) - [1,1' -biphenyl) obtained in example 2]-2-yl) benzamide 1 H-NMR spectrum;
FIG. 4 is a schematic diagram of N- (2' -fluoro-3- (p-toluenesulfonyl) - [ produced in example 21,1' -biphenyls]-2-yl) benzamide 13 C-NMR spectrum;
FIG. 5 is a schematic diagram of N- (2 '-fluoro-3- (p-toluenesulfonyl) - [1,1' -biphenyl) obtained in example 2]-2-yl) benzamide 19 F-NMR spectrum;
FIG. 6 is N- (2-bromo-3-methoxy-6- (p-toluenesulfonyl) phenyl) benzamide prepared in example 3 1 H-NMR spectrum;
FIG. 7 is N- (2-bromo-3-methoxy-6- (p-toluenesulfonyl) phenyl) benzamide prepared in example 3 13 C-NMR spectrum;
FIG. 8 shows N- (1- (p-toluenesulfonyl) naphthalen-2-yl) benzamide obtained in example 4 1 H-NMR spectrum;
FIG. 9 shows N- (1- (p-toluenesulfonyl) naphthalen-2-yl) benzamide obtained in example 4 13 C-NMR spectrum;
FIG. 10 is a drawing of N- (2- ((4-fluorophenyl) sulfinyl) phenyl) benzamide produced in example 5 1 H-NMR spectrum;
FIG. 11 is N- (2- ((4-fluorophenyl) sulfinyl) phenyl) benzamide obtained in example 5 13 C-NMR spectrum;
FIG. 12 is N- (2- ((4-fluorophenyl) sulfinyl) phenyl) benzamide obtained in example 5 19 F-NMR spectrum;
FIG. 13 is a drawing of N- (2- (phenethylsulfinyl) phenyl) benzamide obtained in example 6 1 H-NMR spectrum;
FIG. 14 shows N- (2- (phenethylsulfinyl) phenyl) benzamide obtained in example 6 13 C-NMR spectrum;
Detailed Description
According to the object of the present invention, a method for synthesizing an ortho-aminoaryl sulfoxide compound having a structure represented by formula (III):
in the formula (III), ar is a substituted or unsubstituted aryl, heteroaryl or biaryl, R 1 Is one of benzoyl, acetyl, pivaloyl, ester, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl; r is R 2 Is one of a substituted or unsubstituted aryl, heteroaryl or alkyl group;
the method comprises the following steps:
adding the compound (I) and the compound (II) into a solvent in an air atmosphere, adding alkali into the mixed solution for reaction, and purifying after the reaction is finished to obtain an o-amino aryl sulfoxide compound (III);
according to the present invention, in the following embodiment, the compound (I) has the following structure:
the compound (I) is prepared according to the prior art route, and the preparation route is as follows:
the synthesis steps are as follows: nitro compound (1.0 eq) and 5% rh/C (0.30 mol% rh) were inert gas-shielded (e.g. nitrogen), dissolved with THF (0.5M), then the reaction system was cooled to 0 ℃, and hydrazine hydrate (1.2 eq) was slowly added dropwise; the reaction mixture is stirred for 1 hour at 0 ℃, then slowly warmed to room temperature and stirred for 2 hours at room temperature, the reaction progress can be detected by TLC, after the reaction is finished, the reaction mixture is filtered through kieselguhr, concentrated by rotary evaporation and recrystallized, and the obtained crude hydroxylamine is directly used in the next step;
adding diethyl ether (0.5M) solution into the crude hydroxylamine, and adding saturated NaHCO 3 The aqueous solution was then cooled to 0deg.C, and the corresponding acid chloride (1.1 eq.) was added to the solution, dropwiseAfter completion of the reaction, the mixture was stirred at 0℃for 5 minutes, and then saturated NH for the reaction was used 4 The reaction mixture was extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and after removal of the solvent in vacuo, the crude product was subjected to column chromatography (eluent dichloromethane: ethyl acetate=50:1) or recrystallization to give compound (I).
According to the present invention, in the following embodiment, the compound (II) N-thiophthalimide has the following structure:
the compound (II) is prepared according to the existing technical route of the method 2, and the preparation route is as follows:
method 2:
the synthesis steps are as follows:
method 2: to a dry, argon flushed round bottom flask equipped with a magnetic stir bar and septum was added N-chlorophthalimide (328 mg,5.0mmol,1.0 eq.), dry MeCN (2.6 mL), and pyridine (2.1 mL). Dried MeCN (2.6 mL) and thiophenol/thiol (5.0 mmol,1.0 eq.) in dried pyridine (2.1 mL) were added dropwise at 0 ℃ over 30 min and the resulting mixture stirred for an additional 30 min. After removing most of the MeCN in vacuo, water (20 mL) was added dropwise over 10 minutes at 0 ℃ and stirred for an additional 10 minutes. The resulting suspension was filtered and the filtrate was washed with ice-cold MeOH (3X 5 mL) to give the corresponding N-thiophthalimide compound (II).
According to the invention, the compound (I) is an arylhydroxylamine, which molecules contain a relatively low bond energy nitroxide bond (about 53kcal mol -1 ) The low bond energy of the nitrogen-oxygen bond is caused by the mutual repulsive interaction of the lone pair electron pair on the nitrogen atom and the oxygen atom, the weaker nitrogen-oxygen bond is easy to break in the reaction process, and a new bond with stronger bond energy is easy to form, so that the compound is easy to undergo rearrangement reaction. Aryl hydroxylamine is easy to prepare, functional groupThe compatibility is good, and the o-amino aryl sulfoxide compound can be used as a substrate to widen the group types of the o-amino aryl sulfoxide compound, so that the method is more beneficial to industrial production and application.
The compound (II) is aryl/alkyl N-thiophthalimide, wherein mercapto can generate [2,3] -sigma-rearrangement reaction, and is rearranged in series with the rearrangement reaction of aryl hydroxylamine, so that the smooth synthesis of sulfoxide compounds is realized under the condition of no need of transition metal catalysis and oxidant. Meanwhile, the aryl/alkyl N-thiophthalimide is easy to prepare, has good functional group compatibility, and further widens the group types of the o-amino aryl sulfoxide compound by using the aryl/alkyl N-thiophthalimide as a substrate, thereby being very beneficial to industrial production and application. The by-product phthalimide can be recovered by 85-95% at the end of the reaction of the compound (I) and the compound (II), and can be used for preparing the compound (II) again, thereby further reducing the production cost.
According to the invention, in the ortho-amino aryl sulfoxide compound (III), ar, R 1 From compounds (I), R 2 From the compound (II), ar and R are suitable for the present invention because of good compatibility of the functional groups in the compound (I) and the compound (II) 1 、R 2 The selection range is wide, and the group variety of the o-amino aryl sulfoxide compound is further widened.
In one or more preferred embodiments, the ortho-aminoaryl sulfoxide compound (III) is a substituted phenyl compound
R 3 Is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester group, alkoxy, aryl, heteroaryl, oxytrifluoromethyl and silicon group.
In one or more preferred embodiments, the ortho-amino aryl sulfoxide compound is a substituted phenyl compound (III)
R 4 Is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro and heteroaryl.
In one or more preferred embodiments, the ortho-amino aryl sulfoxide compound (III) is a substituted phenyl compound,
R 5 is one of cyclohexyl, phenethyl and decyl.
In one or more preferred embodiments, the ortho-amino aryl sulfoxide compound (III) has the structure:
according to the present invention, the progress of the reaction can be followed by TLC during the reaction.
In one or more preferred embodiments, the purification method is as follows:
after the reaction is finished, the reaction mixture is concentrated, the crude product is purified and separated by column chromatography, and the eluent of the column chromatography is petroleum ether: ethyl acetate=5:1 to obtain the target compound (III).
According to the invention, the reaction molar ratio of the compound (I) to the compound (II) is 1:1 in theory, in order to fully utilize the aryl hydroxylamine, the compound (II) is properly excessive, and after the reaction is finished, the byproduct phthalimide can be recovered by 85-95%, so that the compound (II) can be prepared again, and the production cost is further reduced. Thus, in one or more preferred embodiments, the molar ratio of compound (I) to compound (II) is 1: (1-2), further preferably 1: (1.1-1.5); most preferably, the molar ratio of compound (I) to compound (II) is 1:1.2.
According to the present invention, the tandem rearrangement reaction is carried out under basic conditions, and different basic environments have an important influence on the yield of the target compound (III). In one or more preferred embodiments, the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium t-butoxide, sodium t-butoxide, or DBU; most preferably, the base is potassium tert-butoxide or DBN.
In one or more preferred embodiments, the molar ratio of compound (I) to base is 0.5: (1-3), further preferably 0.5: (1.1-1.5); most preferably, the molar ratio of compound (I) to base is 1:1.
The reaction solvent also has an important effect on the yield of the target compound (III) according to the invention, in one or more preferred embodiments the solvent is DME (ethylene glycol dimethyl ether), meCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), CHCl 3 Trichloromethane, tolene (toluene), et 2 O (diethyl ether) or THF (tetrahydrofuran); most preferably, the solvent is DME.
According to the present invention, the reaction temperature also has an important effect on the yield of the target compound (III), and the tandem rearrangement of the present invention is more advantageous in improving the reaction yield at low temperatures. In one or more preferred embodiments, the reaction temperature is from-78 ℃ to 25 ℃, further preferably from-70 ℃ to-20 ℃, most preferably-60 ℃.
The invention is further illustrated by, but not limited to, the following specific examples.
EXAMPLE 1N- (2- (p-toluenesulfonyl) phenyl) benzamide
N-hydroxy-N-phenylbenzamide (0.2 mmol,43 mg), 2- (p-toluenesulfonyl) isoindole-1, 3-dione (1.2 equiv,65 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and then potassium tert-butoxide (1.0 equiv,22.5 mg) was added with stirring at-60℃and stirred at-60℃for 12 hours, the progress of the reaction was followed by TLC, after the completion of the reaction, the solvent was removed from the reaction mixture by a rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give N- (2- (p-toluenesulfonyl) phenyl) benzamide as a white powder in 82% yield.
1 H NMR(500MHz,CDCl 3 )δ11.24(s,1H),8.62(dd,J＝8.3,1.2Hz,1H),8.07–7.96(m,2H),7.64–7.46(m,5H),7.40–7.34(m,2H),7.19(td,J＝7.6,1.2Hz,1H),7.12(d,J＝8.1Hz,2H),2.28(s,3H)；
13 C NMR(126MHz,CDCl 3 )δ165.43,141.82,141.06,139.91,134.33,133.35,132.39,130.36,129.10,128.42,128.04,127.74,124.78,123.66,123.36,21.59.
EXAMPLE 2N- (2 '-fluoro-3- (p-toluenesulfonyl) - [1,1' -biphenyl ] -2-yl) benzamide
N-hydroxy-N- (2 '-fluoro- [1,1' -biphenyl ] -2-yl) benzamide (0.2 mmol,62 mg), 2- (p-toluenesulfonyl) isoindole-1, 3-dione (1.2 equiv,65 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and then potassium tert-butoxide (1.0 equiv,22.5 mg) was added thereto with stirring at-60℃for 12 hours, the progress of the reaction was followed by TLC, after completion of the reaction, the solvent was removed from the reaction mixture by rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give N- (2 '-fluoro-3- (p-toluenesulfonyl) - [1,1' -biphenyl ] -2-yl) benzamide as a white powder in a yield of 70%.
1 H NMR(500MHz,Chloroform-d)δ9.01(s,1H),7.75(d,J＝7.8Hz,1H),7.56(d,J＝7.5Hz,3H),7.52–7.44(m,2H),7.38(t,J＝7.6Hz,3H),7.32(d,J＝8.0Hz,2H),7.22(td,J＝5.6,2.8Hz,1H),7.11(t,J＝7.5Hz,1H),7.05(dd,J＝14.6,8.3Hz,3H),2.30(s,3H)；
13 C NMR(126MHz,CDCl 3 )δ164.99,160.08,158.11,141.24,139.47,135.66,135.07,133.72,131.95,131.17,129.95,129.92,129.85,128.58,127.69,127.38,127.15,124.96,124.49,115.88,115.70,21.43；
19 F NMR(471MHz,Chloroform-d)δ-115.42.
EXAMPLE 3N- (2-bromo-3-methoxy-6- (p-toluenesulfonyl) phenyl) benzamide
N- (2-bromo-3-methoxyphenyl) -N-hydroxybenzoamide (0.2 mmol,64 mg), 2- (p-toluenesulfonyl) isoindole-1, 3-dione (1.2 equiv,65 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and potassium tert-butoxide (1.0 equiv,22.5 mg) was added thereto with stirring at-60℃and stirred at-60℃for 12 hours, the progress of the reaction was followed by TLC, after completion of the reaction, the solvent was removed from the reaction mixture by rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give N- (2-bromo-3-methoxy-6- (p-toluenesulfonyl) phenyl) benzamide as a white powder in a yield of 70%.
1 H NMR(500MHz,Chloroform-d)δ9.23(s,1H),7.91(d,J＝7.5Hz,2H),7.56(t,J＝7.8Hz,2H),7.47(t,J＝7.6Hz,2H),7.39(d,J＝8.2Hz,2H),7.11(d,J＝8.1Hz,2H),6.87(d,J＝8.8Hz,1H),3.92(s,3H),2.32(s,3H)；
13 C NMR(126MHz,Chloroform-d)δ165.54,159.49,141.10,139.86,137.36,133.90,133.24,132.25,129.79,128.59,127.88,127.83,124.95,113.46,110.15,56.73,21.36.
EXAMPLE 4N- (1- (p-toluenesulfonyl) naphthalen-2-yl) benzamide
N-hydroxy-N- (naphthalen-2-yl) benzamide (0.2 mmol,53 mg), 2- (p-toluenesulfonyl) isoindole-1, 3-dione (1.2 equiv,65 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and potassium tert-butoxide (1.0 equiv,22.5 mg) was added under stirring at-60℃and stirred at-60℃for 12 hours, the progress of the reaction was followed by TLC, after completion of the reaction, the solvent was removed from the reaction mixture by rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give colorless transparent viscous liquid N- (1- (p-toluenesulfonyl) naphthalen-2-yl) benzamide in 65% yield.
1 H NMR(500MHz,Chloroform-d)δ11.91(s,1H),8.71(d,J＝9.1Hz,1H),8.41(d,J＝8.5Hz,1H),8.05(d,J＝7.2Hz,2H),8.01(d,J＝9.1Hz,1H),7.88(d,J＝8.2Hz,1H),7.65–7.60(m,1H),7.57(t,J＝7.3Hz,1H),7.54–7.49(m,3H),7.32(d,J＝8.3Hz,2H),7.04(d,J＝8.0Hz,2H),2.24(s,3H)；
13 C NMR(126MHz,Chloroform-d)δ165.32,141.40,141.33,139.27,134.06,133.13,132.20,131.67,130.11,130.06,128.93,128.83,128.30,127.63,125.56,124.46,122.22,122.01,121.29,21.31。
Example 5N- (2- ((4-fluorophenyl) sulfinyl) phenyl) benzamide
N-hydroxy-N-phenylbenzamide (0.2 mmol,43 mg), 2- (p-fluorobenzylthio) isoindole-1, 3-dione (1.2 equiv,66 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and potassium tert-butoxide (1.0 equiv,22.5 mg) was added with stirring at-60℃and stirred at-60℃for 12 hours, the progress of the reaction was followed by TLC, after the completion of the reaction, the solvent was removed from the reaction mixture by a rotary evaporator, and the crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1) to give N- (2- ((4-fluorophenyl) sulfinyl) phenyl) benzamide as a white pure product in a yield of 68%.
1 H NMR(500MHz,DMSO-d 6 )δ11.35(s,1H),10.78(s,1H),7.98(d,J＝7.3Hz,1H),7.80(s,4H),7.75(dd,J＝8.0,1.5Hz,1H),7.71–7.65(m,2H),7.65–7.60(m,1H),7.60–7.55(m,2H),7.45(td,J＝7.6,1.2Hz,1H),7.33(t,J＝8.8Hz,1H)；
13 C NMR(126MHz,DMSO-d 6 )δ169.27,165.60,163.50(d,J C-F ＝248.6Hz),140.37(d,J C-F ＝2.8Hz),138.55,136.58,134.29,133.43,132.63,132.37,132.22,128.75,127.53,127.31(d,J C-F ＝9.1Hz),126.82,126.15(d,J C-F ＝6.5Hz),122.93,116.65,116.47；
19 F NMR(471MHz,DMSO-d 6 )δ-109.42。
EXAMPLE 6N- (2- (phenethylsulfinyl) phenyl) benzamide
N-hydroxy-N-phenylbenzamide (0.2 mmol,43 mg), 2- (phenethylthio) isoindole-1, 3-dione (1.2 equiv,66 mg) and ethylene glycol dimethyl ether (2 mL) were added to a 20mL reaction tube, cooled to-60℃and potassium tert-butoxide (1.0 equiv,22.5 mg) was added with stirring at-60℃and stirred at-60℃for 12 hours, the progress of the reaction was followed by TLC, after the completion of the reaction, the solvent was removed from the reaction mixture by rotary evaporator, and the crude product was purified by column chromatography (eluent petroleum ether: ethyl acetate=5:1) to give N- (2- (phenethylsulfinyl) phenyl) benzamide as a white pure product in a yield of 76%.
1 H NMR(500MHz,Chloroform-d)δ11.61(s,1H),8.75(d,J＝8.4Hz,1H),8.15–7.99(m,2H),7.56(d,J＝7.4Hz,2H),7.51(t,J＝7.5Hz,2H),7.27–7.23(m,3H),7.21(d,J＝7.1Hz,1H),7.17–7.08(m,3H),3.51(dt,J＝12.9,7.3Hz,1H),3.21(dt,J＝12.9,8.2Hz,1H),3.00(t,J＝7.8Hz,2H)；
13 C NMR(126MHz,Chloroform-d)δ165.39,141.40,137.94,133.98,132.87,132.26,128.94,128.92,128.57,127.57,127.03,126.57,125.65,123.45,123.05,55.76,29.29。
Test example 1
N-hydroxy-N-phenyl benzamide and N-thiophthalimide are used as raw materials, ethylene glycol dimethyl ether is used as a solvent, the solvent is used with the quantity of A=2 mL, the alkali is used with the quantity of 1.0 equivalent, the reaction temperature is-40 ℃, the reaction is carried out for 6 hours in an air atmosphere, and the influence of the alkali type on the reaction is explored, and the influence is shown in a table 1.
TABLE 1 influence of alkali on the reaction
As can be seen from the experimental results in table 1, t BuOK is the best base for this reaction.
Test example 2
N-hydroxy-N-phenyl benzamide and N-thiophthalimide are used as raw materials, potassium tert-butoxide is used as alkali, the alkali dosage is 1.0 equivalent, the solvent dosage is A=2 mL, the reaction temperature is minus 40 ℃, the reaction is carried out for 6 hours under the air atmosphere, the influence of the solvent type on the reaction is explored, and the alkali dosage is 1.0 equivalent, as shown in table 2.
TABLE 2 influence of solvent on the reaction
From the experimental results in Table 2, it can be seen that DME is the best solvent for this reaction.
Test example 3
N-hydroxy-N-phenyl benzamide and N-thiophthalimide are used as raw materials, potassium tert-butoxide is used as alkali, the dosage of the alkali is 1.0 equivalent, the reaction is carried out for 5min to 12h under the air atmosphere, and the influence of temperature and concentration on the reaction is explored, as shown in table 3.
TABLE 3 influence of temperature and concentration on the reaction
As can be seen from the experimental results in table 3, the reaction was carried out at-60 ℃ and solvent a=dme (2 mL), which is the optimum temperature and concentration for the reaction.

Claims (10)

1. A synthesis method of an o-amino aryl sulfoxide compound, which has a structure shown in a formula (III):
in the formula (III), ar is a substituted or unsubstituted aryl, heteroaryl or biaryl, R 1 Is one of benzoyl, acetyl, pivaloyl, ester, t-butyloxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl; r is R 2 Is one of a substituted or unsubstituted aryl, heteroaryl or alkyl group;
the method comprises the following steps:
adding the compound (I) and the compound (II) into a solvent in an air atmosphere, adding alkali into the mixed solution for reaction, and purifying after the reaction is finished to obtain an o-amino aryl sulfoxide compound (III);
2. the method for synthesizing an o-aminoaryl sulfoxide compound according to claim 1, wherein Ar isR 3 Is one or more of fluorine, chlorine, bromine, iodine, alkyl, ester group, alkoxy, aryl, heteroaryl, oxytrifluoromethyl and silicon group.
3. The method for synthesizing an o-aminoaryl sulfoxide compound according to claim 1, wherein R is 2 Is thatOne of cyclohexyl, phenethyl and decyl, wherein R 4 Is one or more of fluorine, chlorine, bromine, methyl, methoxy, nitro and heteroaryl.
4. The method for synthesizing an ortho-amino aryl sulfoxide compound according to claim 1, wherein the ortho-amino aryl sulfoxide compound has the following structure:
5. the method for synthesizing an o-amino aryl sulfoxide compound according to claim 1, wherein the purification method is as follows:
after the reaction is finished, the reaction mixture is concentrated, the crude product is subjected to column chromatography, and the eluent for column chromatography is petroleum ether: ethyl acetate=5:1 to obtain the target compound (III).
6. The method for synthesizing an ortho-amino aryl sulfoxide compound according to claim 1, wherein the molar ratio of the compound (I) to the compound (II) is 1: (1-2).
7. The method for synthesizing an o-aminoaryl sulfoxide compound according to claim 1, wherein the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, triethylamine, DBN, potassium t-butoxide, sodium t-butoxide, or DBU.
8. The method for synthesizing an ortho-amino aryl sulfoxide compound according to claim 1, wherein the molar ratio of compound (I) to base is 0.5: (1-3).
9. The method for synthesizing an o-aminoaryl sulfoxide compound according to claim 1, wherein the solvent is DME (ethylene glycol dimethyl ether), meCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), or CHCl 3 Trichloromethane, tolene (toluene), et 2 O (diethyl ether) or THF (tetrahydrofuran).
10. The method for synthesizing an o-aminoaryl sulfoxide compound according to claim 1, wherein the reaction temperature is from-78℃to 25 ℃.
CN202311827694.1A 2023-12-28 2023-12-28 Synthesis method of o-amino aryl sulfoxide compound Pending CN117820175A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311827694.1A CN117820175A (en) 2023-12-28 2023-12-28 Synthesis method of o-amino aryl sulfoxide compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311827694.1A CN117820175A (en) 2023-12-28 2023-12-28 Synthesis method of o-amino aryl sulfoxide compound

Publications (1)

Publication Number Publication Date
CN117820175A true CN117820175A (en) 2024-04-05

Family

ID=90522311

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311827694.1A Pending CN117820175A (en) 2023-12-28 2023-12-28 Synthesis method of o-amino aryl sulfoxide compound

Country Status (1)

Country Link
CN (1) CN117820175A (en)

Similar Documents

Publication Publication Date Title
CN114591194B (en) Para-functional arylamine compound and synthesis method thereof
CN107056668A (en) Thiocarbamide is He oxazolidine thioketone and its synthetic method and application
CN113929605B (en) Ortho-sulfonylated arylamine compound and synthesis method thereof
CN108794426B (en) Heterocyclic dithiocarbamate compound and preparation method thereof
JP2015501282A (en) Process for producing optically active β-hydroxy-α-aminocarboxylic acid ester
CN110156641B (en) Synthesis method of substituted guanidine
CN111620896A (en) Preparation method of tetra-coordinated N, N-chelated diaryl borate compound with 8-aminoquinoline derivative as bidentate ligand
CN117820175A (en) Synthesis method of o-amino aryl sulfoxide compound
CN111116461B (en) Palladium-catalyzed o-toluidine amide gamma-C- (sp)3) Synthesis method of H sulfur/selenium ether compound
CN116023359A (en) Synthesis method of aminothiophene compound and aminothiophene compound
CN113045463B (en) Synthesis method of (E) -3-arylthio-2-iodoethyl acrylate compound
CN107629039B (en) The preparation method and intermediate of deuterated acrylamide
CN114634431A (en) Synthetic method of olefin compound containing thioether and sulfone substituent
JP5665041B2 (en) Iodonium compound, production method thereof, functionalized spirocyclic compound and production method thereof
CN111116420B (en) Preparation method of symmetrical urea compound
CN110540516B (en) Preparation method of 1-sulfonylmethyl-3, 4-dihydronaphthalene
CN109810056B (en) S-alkyl-S-quinolyl-N-sulfonyl nitrogen sulfur ylide compound and preparation and application thereof
CN115057848B (en) Axis chiral isopyranone-indole derivative and synthesis method thereof
CN114349803B (en) Method for synthesizing thioglycoside
CN116375602B (en) Method for photochemically synthesizing benzonitrile by using arylthianthrene salt
CN115304557B (en) Enamine derivative and preparation method thereof
CN115028570B (en) Preparation method of (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylate
CN108424391A (en) The double imidazoles chiral ligands of double benzenesulfonyls and its synthetic method
CN108558862B (en) Synthetic method and intermediate of anti-leukemia cancer cell active molecule
CN115368258A (en) Preparation process of amide compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination