CN113200873A - Ortho-position halogenated arylamine compound and synthesis method thereof - Google Patents

Ortho-position halogenated arylamine compound and synthesis method thereof Download PDF

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CN113200873A
CN113200873A CN202110377310.5A CN202110377310A CN113200873A CN 113200873 A CN113200873 A CN 113200873A CN 202110377310 A CN202110377310 A CN 202110377310A CN 113200873 A CN113200873 A CN 113200873A
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compound
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haloarylamine
solvent
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CN113200873B (en
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渠源
孔凡振
李朋涛
齐士林
孔岩
张琳琳
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Shandong Guike New Material Co ltd
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Abstract

The invention relates to an ortho-position halogenated arylamine compound and a synthesis method thereof, wherein the ortho-position halogenated arylamine compound has a structure shown in a formula (III): in the formula (III), X is Cl or Br; ar is one of substituted naphthyl, phenyl and heteroaryl; r is one of benzoyl, acetyl, pivaloyl, ester group, tert-butyloxycarbonyl, carbobenzoxy and methyl. The invention utilizes the cheap and easily obtained dihalogen sulfoxide to react with the aryl hydroxylamine compound, realizes the high-efficiency synthesis of the o-haloarylamine under mild conditions, has good universality and can well tolerate various functional groups.

Description

Ortho-position halogenated arylamine compound and synthesis method thereof
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to an o-halogen (o-chlorine, o-bromine) arylamine compound and a synthesis method thereof.
Background
Aryl halides are very valuable compounds in modern organic chemistry, and they are widely used in transition metal catalyzed cross-coupling reactions as key substrates for the construction of different carbon-carbon, carbon-nitrogen, carbon-oxygen and carbon-sulfur bonds. In addition, aryl halides are also widely used in transition metal-free catalytic conversions, such as nucleophilic aromatic substitution reactions, the preparation of highly active organometallic reagents (e.g., aryl lithium, aryl magnesium reagents) and intermediates in the class of phenylalkynes, and the like. In addition, aryl halide compounds are key components of many natural products, pharmaceuticals, and functional materials. Among these aryl halide compounds, a halogenated aromatic amine is more important for its wide application in the field of dyes and the like.
The introduction of chlorine atoms has a profound effect on enhancing the biological properties of small molecules. Aromatic chlorination reactions may alter the physicochemical properties of the drug, such as pKa effects, metabolic rate, dipole moment, and the like. Indeed, hundreds of aryl chlorides have been approved as clinical drugs to date. The aryl bromide has higher reactivity than the corresponding aryl chloride, and bromine groups in the aromatic bromide can be efficiently and conveniently converted into other functional groups. Aryl chlorides, bromides are therefore more attractive substrates than the corresponding aryl iodides, aryl triflates, from cost and availability considerations. Some of the aromatic ring chlorination, bromination strategies that are currently known are outlined next.
Electrophilic aromatic halogenation is the main strategy for preparing aryl halides, typically using liquid bromine or chlorine; n-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS); peroxide/HBr or DMSO/HBr as the halogenating agent (formula 1).
Figure BDA0003011672030000011
Formula 1 electrophilic aromatic halogenation
While these methods are effective, they have several limitations (1) they generally require the use of highly toxic or hazardous agents; (2) typically only some of the activated aromatic rings are capable of reacting; (3) some undesirable by-products such as polyhalogenated products or the presence of various regioisomers can be produced and can be difficult to separate.
Transition metal catalyzed, directed regioselective hydrohalogenation is also an effective method for the synthesis of ortho-halogenated aromatic compounds (formula 2).
Figure BDA0003011672030000021
Formula 2. transition metal catalyzed Hydrocarbon halogenation
In 2006, the chapter j group made significant progress in this regard. They utilize CuX2(X＝Cl,Br) as a halogen source, palladium acetate with a catalytic amount as a catalyst, and copper acetate with two equivalent weights as an oxidant, under the heating condition of 90 ℃, the ortho-position selective halogenation of the arylamine under the catalysis of palladium by the acetanilide is realized (as shown in a formula 3).
Figure BDA0003011672030000022
Formula 3 palladium catalyzed CuX2Ortho-halogenation of aromatic amines as halogen sources
The Bedford project developed in 2011 a co-catalyzed ortho C — H halogenation reaction of aromatic amines (formula 4) with p-toluenesulfonic acid and palladium acetate. This reaction was carried out at room temperature in an air atmosphere using NXS (X ═ Cl, Br) as a halogen source and toluene as a solvent.
Figure BDA0003011672030000023
Formula 4 palladium catalyzed ortho halogenation of aromatic amines with NXS as halogen source
The defects in the prior art are that the hydrocarbon halogenation reaction catalyzed by the transition metal usually needs to use expensive transition metal catalysts, such as palladium, rhodium and the like, some of the transition metal catalysts need to be heated at high temperature for a long time, and the reaction conditions are harsh.
Recently, various lewis basic organic catalysts have been successfully applied to electrophilic halogenation of aryl compounds, which is a more environmentally friendly approach than metal catalyst systems. However, these strategies are often influenced by specific catalysts and narrow substrate ranges. Therefore, there is still a great need to develop a mild, efficient and regioselective halogenation strategy for aromatic amines.
Disclosure of Invention
Aiming at the defects and shortcomings in the prior art, the invention provides an ortho-halogenated (chloro-bromo) arylamine compound and a synthesis method thereof. Under mild conditions without transition metal and oxidant, by reacting aryl hydroxylamine compounds with dihalo sulfoxide (SOCl)2,SOBr2) The participation of the series rearrangement reaction realizes the ortho-position halogen arylamine compoundHigh efficiency and high regioselectivity.
The technical scheme of the invention is as follows:
an ortho-haloarylamine compound having the structure of formula (III):
Figure BDA0003011672030000031
in the formula (III), X is Cl or Br;
ar is one of substituted naphthyl, phenyl and heteroaryl;
r is one of benzoyl, acetyl, pivaloyl, ester group, tert-butyloxycarbonyl, carbobenzoxy and methyl.
According to the present invention, it is preferable that the ortho-halogen arylamine compound
Figure BDA0003011672030000032
Being substituted naphthyl compounds
Figure BDA0003011672030000033
Or substituted phenyl compounds
Figure BDA0003011672030000034
Or substituted heteroaryl compounds
Figure BDA0003011672030000035
Wherein R is1Is one of fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, ester group, nitro, aryl, heteroaryl, trifluoromethyl, oxygen trifluoromethyl and oxygen difluoromethyl.
According to the present invention, it is preferred that the ortho-halogen arylamine compound has the following structure:
Figure BDA0003011672030000041
according to the invention, the synthesis method of the ortho-halogen arylamine compound comprises the following steps:
adding a solvent into the compound (I) in a nitrogen atmosphere, adding alkali or not adding the alkali, dropwise adding the compound (II) into the mixed solution for reaction, and after the reaction is finished, purifying to obtain a target compound (III);
Figure BDA0003011672030000051
according to the invention, the progress of the reaction can be followed by TLC during the course of the reaction.
According to the invention, the purification method is preferably as follows:
after the reaction is finished, concentrating the reaction mixture by a rotary evaporator, carrying out column chromatography on the crude product, wherein an eluent after the column chromatography is petroleum ether: ethyl acetate 5:1 to obtain the target compound (III).
According to the invention, preferably, the molar ratio of compound (I) to compound (II) is 1: (1-2), more preferably 1: (1.1-1.6); most preferably, when X is Cl, the molar ratio of compound (I) to compound (II) is 1: 1.2; when X is Br, the molar ratio of compound (I) to compound (II) is 1: 1.5.
According to the invention, the base is preferably sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, Et3N, DABCO, DBN or DBU;
most preferably, when X is Cl, adding alkali to react, wherein the alkali is sodium carbonate; when X is Br, the reaction is carried out without adding a base.
According to the invention, preferably, the solvent is MeCN (acetonitrile), DCE (dichloroethane), DCM (dichloromethane), CHCl3(trichloromethane), PhCl (chlorobenzene), Et2O (diethyl ether) or THF (tetrahydrofuran);
most preferably, when X is Cl, the solvent is THF, and when X is Br, the solvent is DCM.
According to the invention, said compound (I) has the following structure:
Figure BDA0003011672030000052
the compounds (I) can be prepared according to the prior art route, which is as follows:
Figure BDA0003011672030000061
the synthesis steps are as follows: in N2The nitro compound (1.0 eq) and 5% Rh/C (0.30 mol% Rh) were dissolved in THF (0.324M) under an atmosphere, and the reaction was subsequently cooled to 0 ℃ and hydrazine hydrate (1.2 eq) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 hour, then slowly warmed to room temperature and stirred at room temperature for 2 hours, after the reaction was complete, the reaction mixture was filtered through celite, concentrated by rotary evaporation, and recrystallized to give the crude hydroxylamine which was used directly in the next step.
To a solution of hydroxylamine in ether (0.5M), saturated NaHCO was added3Aqueous solution, then cooling the solution to 0 ℃, adding the corresponding acid chloride (1.1 eq) to the solution, after the dropwise addition is complete, stirring at 0 ℃ for 10 seconds, and then reacting with saturated NH4After the reaction mixture was quenched with aqueous Cl solution and extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed in vacuo, the crude product was subjected to column chromatography (eluent dichloromethane: ethyl acetate 50:1) to give compound (I).
According to the invention, said compound (II) dihalosulfoxide has the following structure:
Figure BDA0003011672030000062
the compounds (II) are commercially available or can be prepared according to the prior art. The compound (II) used in the present invention is commercially available from Aladdin reagent Co.Ltd and Shanghai Michelin Biotechnology Co.Ltd.
According to the present invention, the reaction temperature is preferably-40 ℃ to 30 ℃, more preferably 0 ℃.
According to the invention, the ortho-halogen arylamine compound has wide application in the fields of drug development, dye, organic synthesis, industry and the like. Indeed, hundreds of aryl chlorides have been approved as clinical drugs to date. Many products of industrial interest, such as pesticides, insecticides, herbicides, pharmaceuticals and pharmaceutically active molecules, flame retardants and other new materials with halogen functionality, contain fragments of aryl chlorides. Meanwhile, the bromo-arylamine compound is also widely applied to cross-coupling reaction catalyzed by transition metal and conversion catalyzed by a plurality of transition metals.
The technical route of the invention is as follows:
Figure BDA0003011672030000071
the invention has the beneficial effects that:
1. the invention reports a transition metal catalysis-free aromatic amine ortho-halogenation strategy. The method utilizes cheap and easily available dihalogen sulfoxide to react with an aryl hydroxylamine compound to realize the high-efficiency synthesis of the o-haloarylamine under mild conditions. The strategy has good universality, various functional groups can be well tolerated, and the functionalized modification of the silicon-containing compound is successfully realized, which is also the basis and key for promoting the further development and application of the silicon-containing compound in the fields of functional materials, electronic devices, life, medical science and the like.
2. The invention has mild reaction condition and no transition metal catalysis. The starting arylhydroxylamine is readily prepared and the dihalosulfoxide is directly commercially available. The invention has universality, and various aryl hydroxylamines including heterocyclic rings and natural product molecules can effectively realize the halogenation of ortho-position carbon-hydrogen bonds, and the ortho-halogenated arylamine compounds with excellent regioselectivity and various structures are prepared with good yield.
Drawings
FIG. 1 shows the preparation of N- (2-chloro-4- (1H-indol-1-yl) phenyl) benzamide prepared in example 11H-NMR spectrum;
FIG. 2 shows the preparation of N- (2-chloro-4- (1H-indol-1-yl) phenyl) benzamide prepared in example 113A C-NMR spectrum;
FIG. 3 shows 2-chloro-N-methyl-4-nitroaniline prepared in example 2Is/are as follows1H-NMR spectrum;
FIG. 4 shows the preparation of 2-chloro-N-methyl-4-nitroaniline from example 213A C-NMR spectrum;
FIG. 5 shows the preparation of N- (2-chloro-6-methoxy-5- (triisopropylsilyl) ethynyl) pyridin-3-yl) benzamide obtained in example 31H-NMR spectrum;
FIG. 6 shows the preparation of N- (2-chloro-6-methoxy-5- (triisopropylsilyl) ethynyl) pyridin-3-yl) benzamide obtained in example 313A C-NMR spectrum;
FIG. 7 shows N- (2-chloro-4- ((3aS,5aR,8aR,8bS) -2,2,7, 7-tetramethyltetrahydro-3 aH-bis ([1,3] s) prepared in example 4]Dioxole) [4,5-b:4',5' -d]Process for preparing pyran-3 a-yl) methoxy) phenyl) benzamide1H-NMR spectrum;
FIG. 8 shows N- (2-chloro-4- ((3aS,5aR,8aR,8bS) -2,2,7, 7-tetramethyltetrahydro-3 aH-bis ([1,3] s) obtained in example 4]Dioxole) [4,5-b:4',5' -d]Process for preparing pyran-3 a-yl) methoxy) phenyl) benzamide13A C-NMR spectrum;
FIG. 9 is a scheme showing that N- (2-chloro-4- ((8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] prepared in example 5]Process for preparing phenanthren-2-yl) oxy) phenyl) benzamides1H-NMR spectrum;
FIG. 10 is a scheme showing that N- (2-chloro-4- ((8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] prepared in example 5]Process for preparing phenanthren-2-yl) oxy) phenyl) benzamides13A C-NMR spectrum;
FIG. 11 is (3S,8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R) -6-methylhept-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-forty-hydrogen-1H-cyclopenta [ a ] a prepared in example 6]Process for preparing phenanthrene-3-yl-4-benzamido-3-chlorobenzoic acid esters1H-NMR spectrum;
FIG. 12 is (3S,8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R) -6-methylhept-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-forty-hydrogen-1H-cyclopenta [ a ] a prepared in example 6]Process for preparing phenanthrene-3-yl-4-benzamido-3-chlorobenzoic acid esters13A C-NMR spectrum;
FIG. 13 shows the preparation of N- (1-bromonaphthalen-2-yl) benzamide obtained in example 71H-NMR spectrum；
FIG. 14 shows the preparation of N- (1-bromonaphthalen-2-yl) benzamide obtained in example 713A C-NMR spectrum;
FIG. 15 shows the preparation of N- (1, 6-dibromonaphthalen-2-yl) benzamide obtained in example 81H-NMR spectrum;
FIG. 16 shows the preparation of N- (1, 6-dibromonaphthalen-2-yl) benzamide obtained in example 813A C-NMR spectrum;
FIG. 17 is a photograph of N- (1-bromo-7-phenylnaphthalen-2-yl) benzamide prepared in example 91H-NMR spectrum;
FIG. 18 is a photograph of N- (1-bromo-7-phenylnaphthalen-2-yl) benzamide prepared in example 913A C-NMR spectrum;
FIG. 19 is a photograph of N- (2,3, 5-tribromophenyl) benzamide obtained in example 101H-NMR spectrum;
FIG. 20 is a photograph of N- (2,3, 5-tribromophenyl) benzamide obtained in example 1013A C-NMR spectrum;
FIG. 21 shows the preparation of N- (2, 5-dibromo-6-methoxypyridin-3-yl) benzamide obtained in example 111H-NMR spectrum;
FIG. 22 shows the preparation of N- (2, 5-dibromo-6-methoxypyridin-3-yl) benzamide obtained in example 1113A C-NMR spectrum;
FIG. 23 is a drawing showing the preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 4-benzamido-3-bromobenzoate prepared in example 121H-NMR spectrum;
FIG. 24 is a drawing showing the preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 4-benzamido-3-bromobenzoate prepared in example 1213C-NMR spectrum.
Detailed Description
The present invention is further illustrated by, but is not limited to, the following specific examples.
Example 1N- (2-chloro-4- (1H-indol-1-yl) phenyl) benzamide
Figure BDA0003011672030000081
After N- (4- (1H-indol-1-yl) phenyl) -N-hydroxybenzamide (0.2mmol,66mg) and sodium carbonate (0.1mmol) were added to a 25mL Schlenk tube, nitrogen was purged three times, tetrahydrofuran (1mL) was added under a nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise under stirring at 0 ℃, after completion of the dropwise addition, the progress of the reaction was followed by TLC, and after completion of the reaction, the reaction mixture was freed of the solvent by rotary evaporation, and the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate ═ 5:1) to give N- (2-chloro-4- (1H-indol-1-yl) phenyl) benzamide as a pure white powder in 66% yield.
1H NMR(500MHz,CDCl3):δ8.63(d,J＝8.8Hz,1H),8.39(s,1H),7.90-7.81(m,2H),7.60(d,J＝7.8Hz,1H),7.55-7.47(m,2H),7.45(t,J＝7.6Hz,3H),7.39(dd,J＝8.8,2.4Hz,1H),7.20(t,J＝3.8Hz,1H),7.19-7.13(m,1H),7.12-7.06(m,1H),6.60(d,J＝3.2Hz,1H)。
13C NMR(126MHz,CDCl3):δ165.4,136.2,135.8,134.4,133.1,132.4,129.4,129.1,127.7,127.2,124.7,123.8,123.7,122.8,122.4,121.3,120.7,110.3,104.2。
Example 2, 2-chloro-N-methyl-4-nitroaniline
Figure BDA0003011672030000091
After N-methyl-N- (4-nitrophenyl) hydroxylamine (0.2mmol,34mg) and sodium carbonate (0.1mmol) were added to a 25mL Schlenk tube, nitrogen was purged three times, tetrahydrofuran (1mL) was added under a nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise under stirring at 0 ℃, after completion of the dropwise addition, the reaction progress was followed by TLC, after completion of the reaction, the reaction mixture was subjected to rotary evaporation to remove the solvent, and the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate: 5:1) to obtain 2-chloro-N-methyl-4-nitroaniline as a colorless oily pure product with a yield of 65%.
1H NMR(500MHz,CDCl3):δ8.19(d,J＝2.5Hz,1H),8.09(dd,J＝9.1,2.5Hz,1H),6.60(d,J＝9.1Hz,1H),5.16(s,1H),3.02(d,J＝5.0Hz,3H)。
13C NMR(126MHz,CDCl3):δ149.8,137.4,125.3,124.9,117.8,108.4,30.2。
Example 3N- (2-chloro-6-methoxy-5- (triisopropylsilyl) ethynyl) pyridin-3-yl) benzamide
Figure BDA0003011672030000092
In a 25mL Schlenk tube, N-hydroxy-N- (6-methoxy-5- (triisopropylsilyl) ethynyl) pyridin-3-yl) benzamide (0.2mmol,85mg) and sodium carbonate (0.1mmol) were added, after purging with nitrogen three times, tetrahydrofuran (1mL) was added under nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise with stirring at 0 ℃, after completion of the dropwise addition, the progress of the reaction was followed by TLC, after completion of the reaction, the reaction mixture was freed of solvent by rotary evaporation, the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate 5:1) pure N- (2-chloro-6-methoxy-5- (triisopropylsilyl) ethynyl) pyridin-3-yl) benzamide was obtained as a white powder in 95% yield.
1H NMR(500MHz,CDCl3):δ8.81(s,1H),8.10(s,1H),7.90(d,J＝7.6Hz,2H),7.59(t,J＝7.3Hz,1H),7.52(t,J＝7.6Hz,2H),3.97(s,3H),1.14(s,21H)。
13C NMR(126MHz,CDCl3):δ164.3,158.7,135.1,134.9,132.9,131.4,128.0,126.0,123.9,106.1,98.9,97.6,53.7,17.6,10.3。
Example 4N- (2-chloro-4- ((3aS,5aR,8aR,8bS) -2,2,7, 7-tetramethyltetrahydro-3 aH-bis ([1,3] dioxole) [4,5-b:4',5' -d ] pyran-3 a-yl) methoxy) phenyl) benzamide
Figure BDA0003011672030000101
N-hydroxy-N- (4- ((3aS,5aR, 8bS) -2,2,7, 7-tetramethyltetrahydro-3 aH-bis ([1,3] dioxole) [4,5-b:4',5' -d ] pyran-3 a-yl) methoxy) phenyl) benzamide (0.2mmol,94mg) and sodium carbonate (0.1mmol) were added to a 25mL Schlenk tube, after purging with nitrogen three times, tetrahydrofuran (1mL) was added to a nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise with stirring at 0 ℃, after completion of dropwise addition, the progress of the reaction was followed by TLC, after completion of the reaction, the reaction mixture was freed of the solvent by rotary evaporation, and the crude product was subjected to column chromatography (eluent was petroleum ether: ethyl acetate 5:1) pure N- (2-chloro-4- ((3aS,5aR, 8bS) -2,2,7, 7-tetramethyltetrahydro-3 aH-bis ([1,3] dioxole) [4,5-b:4',5' -d ] pyran-3 a-yl) methoxy) phenyl) benzamide was obtained aS a white powder in 83% yield.
1H NMR(500MHz,CDCl3):δ8.37(d,J＝9.1Hz,1H),8.23(s,1H),7.94-7.84(m,2H),7.58-7.52(m,1H),7.52-7.45(m,2H),7.02(d,J＝2.8Hz,1H),6.91(dd,J＝9.1,2.8Hz,1H),4.64(dd,J＝7.9,2.6Hz,1H),4.51(d,J＝2.6Hz,1H),4.26(dd,J＝7.9,1.2Hz,1H),4.14(d,J＝10.2Hz,1H),4.04(d,J＝10.2Hz,1H),3.96(dd,J＝13.0,1.8Hz,1H),3.79(d,J＝13.0Hz,1H),1.56(s,3H),1.50(s,3H),1.46(s,3H),1.35(s,3H)。
13C NMR(126MHz,CDCl3):δ165.2,155.3,134.7,132.0,128.9,128.5,127.1,124.3,123.0,115.5,114.1,109.1,109.0,102.0,70.9,70.1,70.0,69.5,61.3,26.6,26.0,25.3,24.0。
Example 5N- (2-chloro-4- ((8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-2-yl) oxy) phenyl) benzamide
Figure BDA0003011672030000111
In a 25mL Schlenk tube, N-hydroxy-N- (4- ((8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-2-yl) oxy) phenyl) benzamide (0.2mmol,96mg) and sodium carbonate (0.1mmol) were added, after purging with nitrogen three times, tetrahydrofuran (1mL) was added in a nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise under stirring at 0 ℃, after completion of dropwise addition, the progress of the reaction was followed by TLC, after completion of the reaction, the reaction mixture was freed of the solvent by rotary evaporation, and the crude product was subjected to (eluent for column chromatography: ethyl acetate 5:1) pure N- (2-chloro-4- ((8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-2-yl) oxy) phenyl) benzamide was obtained as a white powder in 78% yield.
1H NMR(500MHz,CDCl3):δ8.43(d,J＝9.0Hz,1H),8.32(s,1H),7.91(dd,J＝5.2,3.3Hz,2H),7.62-7.54(m,1H),7.54-7.46(m,2H),7.26(d,J＝8.5Hz,1H),7.08(d,J＝2.7Hz,1H),6.98(dd,J＝9.0,2.7Hz,1H),6.81(dd,J＝8.5,2.7Hz,1H),6.75(d,J＝2.6Hz,1H),2.92-2.83(m,2H),2.50(dd,J＝19.0,8.6Hz,1H),2.41(ddd,J＝10.2,7.1,3.6Hz,1H),2.28(td,J＝10.9,4.0Hz,1H),2.20-2.10(m,1H),2.04-1.93(m,2H),1.72-1.37(m,7H),0.93(s,3H)。
13C NMR(126MHz,CDCl3):δ165.2,154.6,154.1,138.5,135.4,134.6,132.2,130.0,128.9,127.1,126.8,124.3,123.0,119.2,119.0,118.0,116.4,50.5,48.0,44.1,38.2,35.9,31.6,29.5,26.4,25.9,21.6,13.9。
Example 6, (3S,8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-forty-hydro-1H-cyclopenta [ a ] phenanthren-3-yl-4-benzamido-3-chlorobenzoate
Figure BDA0003011672030000112
(3S,8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecyl-1H-cyclopenta [ a ] phenanthren-3-yl-4- (N-hydroxybenzamido) benzoate (0.2mmol,125mg) and sodium carbonate (0.1mmol) were added to a 25mL Schlenk tube, after purging with nitrogen three times, tetrahydrofuran (1mL) was added under a nitrogen atmosphere, after cooling to 0 ℃, thionyl chloride (0.24mmol) was added dropwise with stirring at 0 ℃, after completion of dropwise addition, the progress of the reaction was followed by TLC, after completion of the reaction, the reaction mixture was freed from the solvent by rotary evaporation, the crude product was subjected to column chromatography (eluent: petroleum ether: ethyl acetate ═ 5:1) to give pure (3S,8S,9S,10R,13R,14S,17R) -10, 13-dimethyl-17- ((R) -6-methylhept-2-yl) -2,3,4,7,8,9,10,11,12,13,14,15,16, 17-forty-hydro-1H-cyclopenta [ a ] phenanthren-3-yl-4-benzoylamino-3-chlorobenzoate as a white powder in 55% yield.
1H NMR(500MHz,CDCl3):δ8.71(d,J＝8.7Hz,1H),8.63(s,1H),8.10(d,J＝1.9Hz,1H),8.00(dd,J＝8.7,1.9Hz,1H),7.95-7.88(m,2H),7.65-7.56(m,1H),7.53(dd,J＝10.4,4.7Hz,2H),5.42(d,J＝4.5Hz,1H),4.94-4.71(m,1H),2.47(d,J＝7.9Hz,2H),2.08-1.95(m,3H),1.92(dt,J＝13.2,3.3Hz,1H),1.88-1.80(m,1H),1.79-1.72(m,1H),1.72-1.42(m,7H),1.41-1.32(m,3H),1.22-0.97(m,13H),0.92(d,J＝6.5Hz,3H),0.87(dd,J＝6.6,2.2Hz,6H),0.69(s,3H)。
13C NMR(126MHz,CDCl3):δ165.2,164.4,139.6,138.5,134.2,132.6,130.3,129.5,129.1,127.2,126.9,122.9,122.4,120.2,75.0,56.7,56.2,50.1,42.4,39.8,39.5,38.2,37.0,36.7,36.2,35.8,32.0,31.9,28.3,28.0,27.9,24.3,23.9,22.8,22.6,21.1,19.4,18.8,11.9。
Example 7N- (1-Bromomaphthalen-2-yl) benzamide
Figure BDA0003011672030000121
After N-hydroxy-N- (naphthalen-2-yl) benzamide (0.2mmol,53mg) was added to a 25mL Schlenk tube and nitrogen was purged three times, dichloromethane (2mL) was added under nitrogen, the mixture was cooled to 0 ℃, dibromosulfoxide (0.24mmol) was added dropwise at 0 ℃ with stirring, after completion of the dropwise addition, the mixture was moved to room temperature and the progress of the reaction was followed by TLC, after completion of the reaction, the reaction mixture was subjected to rotary evaporation to remove the solvent, and the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate: 5:1) to obtain pure N- (1-bromonaphthalen-2-yl) benzamide as a white powder with a yield of 97%.
1H NMR(500MHz,CDCl3):δ8.76(s,1H),8.69(d,J＝9.0Hz,1H),8.19(d,J＝8.5Hz,1H),8.06-7.97(m,2H),7.86(dd,J＝19.4,8.5Hz,2H),7.66-7.52(m,4H),7.52-7.44(m,1H)。
13C NMR(126MHz,CDCl3):δ165.4,134.7,134.5,132.3,132.0,131.7,129.0,128.5,128.2,127.8,127.3,126.6,125.6,120.8,112.1。
Example 8N- (1, 6-Dibromonaphthalen-2-yl) benzamide
Figure BDA0003011672030000122
Adding N- (6-bromonaphthalene-2-yl) -N-hydroxybenzamide (0.2mmol,68mg) into a 25mL Schlenk tube, vacuumizing for three times by using nitrogen, adding dichloromethane (2mL) into a nitrogen atmosphere, cooling to 0 ℃, dropwise adding dibromosulfoxide (0.24mmol) under the condition of 0 ℃ while stirring, moving to room temperature after dropwise adding is finished, tracking the reaction process by TLC, removing the solvent from the reaction mixture by rotary evaporation after the reaction is finished, and performing column chromatography on the crude product (an eluent is petroleum ether and ethyl acetate is 5:1) to obtain a white powdery pure product N- (1, 6-dibromonaphthalene-2-yl) benzamide, wherein the yield is 86%.
1H NMR(500MHz,CDCl3):δ8.74-8.65(m,2H),8.06-7.93(m,4H),7.74(d,J＝9.0Hz,1H),7.66-7.57(m,2H),7.54(dd,J＝10.3,4.6Hz,2H)。
13C NMR(126MHz,CDCl3):δ165.4,134.9,134.5,132.4,131.1,130.6,130.1,129.0(2C),128.4,127.5,127.2,121.8,119.8,111.9。
Example 9N- (1-bromo-7-phenylnaphthalen-2-yl) benzamide
Figure BDA0003011672030000131
After N-hydroxy-N- (7-phenylnaphthalen-2-yl) benzamide (0.2mmol,68mg) was added to a 25mL Schlenk tube and nitrogen was purged three times, dichloromethane (2mL) was added under a nitrogen atmosphere, after cooling to 0 ℃, dibromosulfoxide (0.24mmol) was added dropwise under stirring at 0 ℃, after completion of the dropwise addition, the reaction mixture was moved to room temperature and followed by TLC, after completion of the reaction, the solvent was removed from the reaction mixture by rotary evaporation, and the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate: 5:1) to obtain pure N- (1-bromo-7-phenylnaphthalen-2-yl) benzamide as a white powder with a yield of 85%.
1H NMR(500MHz,DMSO-d6):δ10.33(s,1H),8.41(s,1H),8.10(t,J＝7.4Hz,3H),8.04(d,J＝8.7Hz,1H),7.92(dd,J＝8.5,1.5Hz,1H),7.81(d,J＝7.4Hz,2H),7.74(d,J＝8.6Hz,1H),7.63(t,J＝7.3Hz,1H),7.59-7.50(m,4H),7.43(t,J＝7.3Hz,1H)。
13C NMR(126MHz,DMSO-d6):δ165.9,140.2,136.1,134.5,132.6,132.4,132.0,129.73,129.68,129.0(2C),128.5,128.3,128.2,127.7,127.2,126.3,124.5,119.9。
Example 10N- (2,3, 5-Tribromophenyl) benzamide
Figure BDA0003011672030000132
After N- (3, 5-dibromophenyl) -N-hydroxybenzamide (0.2mmol,74mg) is added into a 25mL Schlenk tube, nitrogen is pumped out for three times, dichloromethane (2mL) is added into the nitrogen atmosphere, after the mixture is cooled to 0 ℃, dibromosulfoxide (0.24mmol) is added dropwise under the condition of 0 ℃ while stirring, after the dropwise addition is completed, the mixture is moved to room temperature, the reaction process is tracked by TLC, after the reaction is completed, the reaction mixture is removed by rotary evaporation, and the crude product is subjected to column chromatography (eluent is petroleum ether, ethyl acetate is 5:1) to obtain pure N- (2,3, 5-tribromophenyl) benzamide of white powder with the yield of 50%.
1H NMR(500MHz,CDCl3):δ8.80(d,J＝2.2Hz,1H),8.58(s,1H),7.96-7.86(m,2H),7.64-7.58(m,1H),7.57(d,J＝2.2Hz,1H),7.56-7.51(m,2H)。
13C NMR(126MHz,CDCl3):δ165.3,138.3,133.9,132.7,131.0,129.1,127.2,125.5,122.7,122.4,115.1。
Example 11N- (2, 5-dibromo-6-methoxypyridin-3-yl) benzamide
Figure BDA0003011672030000141
After N- (5-bromo-6-methoxypyridin-3-yl) -N-hydroxybenzamide (0.2mmol,64mg) was added to a 25mL Schlenk tube and nitrogen was purged three times, methylene chloride (2mL) was added under nitrogen atmosphere, and after cooling to 0 ℃, dibromosulfoxide (0.24mmol) was added dropwise under stirring at 0 ℃, after completion of the dropwise addition, the reaction mixture was moved to room temperature and followed by TLC, after completion of the reaction, the solvent was removed by rotary evaporation from the reaction mixture, and the crude product was subjected to column chromatography (eluent petroleum ether: ethyl acetate: 5:1) to obtain pure N- (2, 5-dibromo-6-methoxypyridin-3-yl) benzamide as a white powder in 53% yield.
1H NMR(500MHz,DMSO-d6):δ10.20(s,1H),8.21(s,1H),7.99(d,J＝7.5Hz,2H),7.62(t,J＝7.3Hz,1H),7.54(t,J＝7.5Hz,2H),3.96(s,3H)。
13C NMR(126MHz,DMSO-d6):δ166.2,157.4,143.3,136.1,133.9,132.5,129.0,128.9,128.2,104.7,55.8。
Example 12, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 4-benzamido-3-bromobenzoate
Figure BDA0003011672030000142
Adding (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 4- (N-hydroxybenzamido) benzoate (0.2mmol,79mg) into a 25mL Schlenk tube, vacuumizing with nitrogen for three times, adding dichloromethane (2mL) into a nitrogen atmosphere, cooling to 0 ℃, dropwise adding dibromosulfoxide (0.24mmol) under the condition of 0 ℃ while stirring, moving to room temperature after dropwise adding, tracking the reaction progress by TLC, removing the solvent from the reaction mixture after the reaction is completed by rotary evaporation, subjecting the crude product to column chromatography (eluent is petroleum ether: ethyl acetate: 5:1) to obtain a white powdery pure product (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 4-benzoylamido-3-bromobenzoate), the yield thereof was found to be 54%.
1H NMR(500MHz,CDCl3):δ8.70(d,J＝8.7Hz,1H),8.66(s,1H),8.26(d,J＝1.6Hz,1H),8.04(dd,J＝8.7,1.7Hz,1H),7.95(d,J＝7.5Hz,2H),7.61(t,J＝7.2Hz,1H),7.54(t,J＝7.7Hz,2H),4.94(td,J＝10.9,4.4Hz,1H),2.11(d,J＝12.0Hz,1H),1.93(dtd,J＝13.9,6.9,2.6Hz,1H),1.74(dd,J＝9.1,7.0Hz,2H),1.61-1.50(m,2H),1.20-1.06(m,2H),0.93(dd,J＝6.7,4.3Hz,7H),0.80(d,J＝6.9Hz,3H)。
13C NMR(126MHz,CDCl3):δ165.3,164.4,139.5,134.2,133.6,132.6,130.1,129.1,127.4,127.2,120.4,112.9,75.3,47.3,41.0,34.3,31.5,26.6,23.7,22.0,20.8,16.5。
Test example 1
N-hydroxy-N- (naphthalene-2-yl) benzamide and thionyl chloride are used as raw materials, tetrahydrofuran is used as a solvent, the amount of the solvent is 1mL, the amount of base is 2 equivalents, the reaction temperature is 0 ℃, the reaction is carried out for 1h under a nitrogen atmosphere, and the influence of the type of the base on the reaction is researched, as shown in Table 1-1.
TABLE 1-1 Effect of bases on the reaction
Figure BDA0003011672030000151
As can be seen from the results of the experiment in Table 1-1, when X is Cl, Na is present2CO3Is the optimal base for this reaction.
Test example 2
Taking N-hydroxy-N- (naphthalene-2-yl) benzamide and thionyl chloride as raw materials, Na2CO3The reaction is carried out for 1h under the nitrogen atmosphere, the influence of the type of the solvent on the reaction is researched, and the dosage of the alkali is 2 equivalents, the dosage of the solvent is 1mL, the reaction temperature is 0 ℃, and the dosage of the alkali is 2 equivalents as shown in a table 1-2.
TABLE 1-2 Effect of solvent on the reaction
Figure BDA0003011672030000161
As can be seen from the results of the experiments in tables 1-2, when X is Cl, none of the above solvents is as effective as THF, which is the best solvent for the reaction.
Test example 3
Taking N-hydroxy-N- (naphthalene-2-yl) benzamide and thionyl chloride as raw materials, Na2CO3The base is 2 equivalents, THF is solvent, the solvent is 1mL, the reaction temperature is 0 ℃, and the nitrogen atmosphere is adoptedThe reaction was carried out for 1h, and the effect of the amount of the base on the reaction was investigated, as shown in tables 1-3.
TABLE 1-3 Effect of the amount of base used on the reaction
Figure BDA0003011672030000162
As can be seen from the results of the experiments in tables 1 to 3, when X is Cl, the amount of the base used is 0.5 equivalent, which is most advantageous for the reaction.
Test example 4
N-hydroxy-N- (naphthalene-2-yl) benzamide and dibromosulfoxide are used as raw materials, sodium carbonate is used as alkali, the amount of the alkali is 2 equivalents, the reaction temperature is-20 ℃, the reaction is carried out for 0.5h under the nitrogen atmosphere, and the influence of the type of the solvent on the reaction is researched, as shown in Table 2-1.
TABLE 2-1 Effect of solvent on the reaction
Figure BDA0003011672030000171
As can be seen from the experimental results of Table 2-1, DCM is the best solvent for the reaction when X is Br.
Test example 5
N-hydroxy-N- (naphthalene-2-yl) benzamide and dibromosulfoxide are used as raw materials, DCM is used as a solvent, the dosage of the solvent is 1mL, the reaction temperature is-20 ℃, the reaction is carried out for 0.5h under the nitrogen atmosphere, the influence of the type of alkali on the reaction is researched, and the dosage of the alkali is 2 equivalents, which is shown in Table 2-2.
TABLE 2-2 Effect of base on the reaction
Figure BDA0003011672030000172
Figure BDA0003011672030000181
As can be seen from the results of the experiments in Table 2-2, when X is Br, the reaction proceeds smoothly without addition of an alkali.
Test example 6
N-hydroxy-N- (naphthalene-2-yl) benzamide and dibromosulfoxide are used as raw materials, no alkali is added, DCM is used as a solvent, the dosage of the solvent is 1mL, the reaction is carried out for 0.5h under the nitrogen atmosphere, and the influence of the temperature on the reaction is researched, as shown in tables 2-3.
TABLE 2-3 Effect of temperature on the reaction
Figure BDA0003011672030000182
As can be seen from the results of the experiments in tables 2 to 3, when X is Br, the reaction is most favorably carried out by adding dibromosulfoxide at 0 ℃ and then moving to room temperature.

Claims (10)

1. An ortho-haloarylamine compound characterized by having a structure represented by formula (iii):
Figure FDA0003011672020000011
in the formula (III), X is Cl or Br;
ar is one of substituted naphthyl, phenyl and heteroaryl;
r is one of benzoyl, acetyl, pivaloyl, ester group, tert-butyloxycarbonyl, carbobenzoxy and methyl.
2. A ortho-haloarylamine compound according to claim 1 wherein said ortho-haloarylamine compound is a halogenated arylamine compound
Figure FDA0003011672020000012
Being substituted naphthyl compounds
Figure FDA0003011672020000013
Or substituted phenyl compounds
Figure FDA0003011672020000014
Or substituted heteroaryl compounds
Figure FDA0003011672020000015
Wherein R is1Is one of fluorine, chlorine, bromine, iodine, alkyl, alkenyl, alkynyl, ester group, nitro, aryl, heteroaryl, trifluoromethyl, oxygen trifluoromethyl and oxygen difluoromethyl.
3. A ortho-haloarylamine compound in accordance with claim 1, wherein said ortho-haloarylamine compound has the structure:
Figure FDA0003011672020000021
4. a process for the synthesis of a vicinal haloarylamine compound according to claim 1 comprising the steps of:
adding a solvent into the compound (I) in a nitrogen atmosphere, adding alkali or not adding the alkali, dropwise adding the compound (II) into the mixed solution for reaction, and after the reaction is finished, purifying to obtain a target compound (III);
Figure FDA0003011672020000031
5. a process for the synthesis of a vicinal haloarylamine compound according to claim 4 wherein the purification process is as follows:
after the reaction is finished, concentrating the reaction mixture by a rotary evaporator, carrying out column chromatography on the crude product, wherein an eluent after the column chromatography is petroleum ether: ethyl acetate 5:1 to obtain the target compound (III).
6. A process for the synthesis of a vicinal haloarylamine compound according to claim 4 wherein the molar ratio of compound (I) to compound (II) is 1: (1-2).
7. A process for the synthesis of ortho-haloarylamine compounds according to claim 4 wherein when X is Cl, the molar ratio of compound (I) to compound (II) is 1: 1.2; when X is Br, the molar ratio of compound (I) to compound (II) is 1: 1.5.
8. The method for synthesizing an ortho-haloarylamine compound according to claim 4, wherein the base is sodium carbonate, potassium phosphate, sodium bicarbonate, pyridine, DMAP, Et3N, DABCO, DBN or DBU;
preferably, when X is Cl, adding alkali to react, wherein the alkali is sodium carbonate; when X is Br, the reaction is carried out without adding a base.
9. A process according to claim 4, wherein the solvent is MeCN, DCE, DCM, CHCl3、PhCl、Et2O or THF;
preferably, when X is Cl, the solvent is THF, and when X is Br, the solvent is DCM.
10. A process for the synthesis of an ortho-haloarylamine compound according to claim 4 wherein the reaction temperature is from-40 ℃ to 30 ℃.
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